Aryl- or heteroaryl-sulfonyl compounds as acid secretion inhibitors

ABSTRACT

The present invention provides a compound having a superior acid secretion inhibitory action, an antiulcer activity and the like. 
     A proton pump inhibitor containing a compound represented by the formula (I) 
     
       
         
         
             
             
         
       
     
     wherein ring A is a saturated or unsaturated 5- or 6-membered ring group optionally having, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, ring-constituting atoms X 1  and X 2  are each a carbon atom or a nitrogen atom, a ring-constituting atom X 3  is a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, R 1  is an optionally substituted aryl group or an optionally substituted heteroaryl group, R 2  is an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group, R 3  is an aminomethyl group optionally substituted by 1 or 2 lower alkyl groups, which is a substituent on a ring-constituting atom other than X 1 , X 2  and X 3 , and ring A optionally further has substituent(s) selected from a lower alkyl group, a halogen atom, a cyano group and an oxo group, or a salt thereof or a prodrug thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 12/225,851, filed Sep. 30, 2008, allowed, which is the nationalstage application pursuant to 35 U.S.C. §371 of PCT Application No.PCT/JP2007/057102, filed Mar. 30, 2007, which claims priority toJapanese Patent Application No. 100651/2006, filed Mar. 31, 2006. Thecontents of the foregoing applications are hereby incorporated byreference in their entirety.

TECHNICAL FIELD

The present invention relates to a compound having an acid secretioninhibitory activity.

BACKGROUND ART

Proton pump inhibitors represented by omeprazole, which suppresssecretion of gastric acid for the treatment of peptic ulcer, refluxesophagitis and the like, have been widely used in clinical situations.However, the existing proton pump inhibitors are associated withproblems in terms of effect and side effects. To be specific, since theexisting proton pump inhibitors are unstable under acidic conditions,they are often formulated as enteric preparations, in which case severalhours are required before expression of the effect. In addition, sincethe existing proton pump inhibitors show inconsistent treatment effectsdue to metabolic enzyme polymorphism and drug interaction withpharmaceutical agents such as diazepam and the like, an improvement hasbeen desired.

As a compound having a proton pump inhibitory action, a thiazolederivative is described in patent reference 1.

As a compound having a thromboxane A2 (TXA2) antagonistic action andTXA2 synthase inhibitory action, patent reference 2 describes a compoundrepresented by the formula

wherein r1 is carboxy, protected carboxy, carboxy(lower)alkyl, protectedcarboxy(lower)alkyl, carboxy(lower)alkenyl or protectedcarboxy(lower)alkenyl, r2 is hydrogen; lower alkyl; aminoimino orheterocyclic (lower)alkyl optionally having protected aminoimino;heterocyclic (lower)alkenyl; or heterocyclic carbonyl, r3 is hydrogen orlower alkyl, r4 is acyl, r5 is hydrogen, A₀ is lower alkylene, Z₀ is Sor NH, and when r1 is carboxy or protected carboxy, then Z₀ is NH.

As a therapeutic drug for neoplastic diseases and autoimmune diseases,patent reference 3 describes a compound represented by the formula

wherein r6 is aryl, aralkyl or heteroaryl, r7 is aryl or heteroaryl, andr8 is aryl, heteroaryl or optionally substituted aminomethyl.

In addition, patent reference 4 describes a pyridyl or imidazolylderivative having a protein•isoprenyl•transferase inhibitory action.

-   patent reference 1: EP-A-0259085-   patent reference 2: JP-A-8-119936-   patent reference 3: WO2004/103968-   patent reference 4: US2002/0193596

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

A pharmaceutical agent that effectively suppresses gastric acidsecretion as known proton pump inhibitors, which is improved ininstability under acidic conditions, dispersion of effects due tometabolic enzyme polymorphism and drug interaction, which are problemsof known proton pump inhibitors, is expected to show more superiortreatment effect on peptic ulcer, erosive esophagitis and the like. Asthe situation stands, however, a proton pump inhibitor capable ofsufficiently satisfying these requirements has not been found. It istherefore an object of the present invention to provide a compoundhaving a superior acid secretion suppressive effect (particularly,proton pump inhibitory action), which has been improved in theseproblems.

Means of Solving the Problems

The present inventors have conducted various studies and found that acompound represented by the formula (I):

wherein ring A is a saturated or unsaturated 5- or 6-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, ring-constituting atoms X₁ and X₂ are each a carbon atom ora nitrogen atom, a ring-constituting atom X₃ is a carbon atom, anitrogen atom, an oxygen atom or a sulfur atom, R¹ is an optionallysubstituted aryl group or an optionally substituted heteroaryl group, R²is an optionally substituted alkyl group, an optionally substituted arylgroup or an optionally substituted heteroaryl group, R³ is anaminomethyl group optionally substituted by 1 or 2 lower alkyl groups,which is a substituent on a ring-constituting atom other than X₁, X₂ andX₃, and ring A optionally further has substituent(s) selected from alower alkyl group, a halogen atom, a cyano group and an oxo group,excluding a compound represented by the formula

wherein each symbol is as defined above, a pyrrole ring optionallyfurther has substituent(s) selected from a lower alkyl group, a halogenatom, a cyano group and an oxo group, or a salt thereof [hereinafter tobe abbreviated as compound (I)] unexpectedly has a highly strong acidsecretion inhibitory action (proton pump inhibitory action), and issufficiently satisfactory as a pharmaceutical agent, based on whichfindings the present invention has been completed.

Accordingly, the present invention relates to

[1] an acid secretion inhibitor comprising a compound represented by theformula (I)

wherein ring A is a saturated or unsaturated 5- or 6-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, ring-constituting atoms X₁ and X₂ are each a carbon atom ora nitrogen atom, a ring-constituting atom X₃ is a carbon atom, anitrogen atom, an oxygen atom or a sulfur atom, R¹ is an optionallysubstituted aryl group or an optionally substituted heteroaryl group, R²is an optionally substituted alkyl group, an optionally substituted arylgroup or an optionally substituted heteroaryl group, R³ is anaminomethyl group optionally substituted by 1 or 2 lower alkyl groups,which is a substituent on a ring-constituting atom other than X₁, X₂ andX₃, ring A optionally further has substituent(s) selected from a loweralkyl group, a halogen atom, a cyano group and an oxo group, excluding acompound represented the formula

wherein each symbol is as defined above, a pyrrole ring optionallyfurther has substituent(s) selected from a lower alkyl group, a halogenatom, a cyano group and an oxo group, or a salt thereof, or a prodrugthereof,[2] the acid secretion inhibitor of the above-mentioned [1], wherein thecompound represented by the formula (I) is a compound represented by theformula

wherein ring C is a saturated or unsaturated 5-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, ring D is a saturated or unsaturated 6-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, R^(1a) and R^(1b) are each an optionally substituted arylgroup or an optionally substituted heteroaryl group, R^(2a) and R^(2b)are each an optionally substituted alkyl group, an optionallysubstituted aryl group or an optionally substituted heteroaryl group,R^(6a), R^(7a), R^(6b) and R^(7b) are each absent, or a hydrogen atom, alower alkyl group, a halogen atom or a cyano group, R^(3a) and R^(3b)are each an aminomethyl group optionally substituted by 1 or 2 loweralkyl groups, and R^(8b) is absent or a hydrogen atom, a lower alkylgroup, a halogen atom, a cyano group or an oxo group, excluding acompound represented by the formula

wherein each symbol is as defined above,[3] the acid secretion inhibitor of the above-mentioned [2], wherein thecompound is a compound represented by the formula (Ia),[4] the acid secretion inhibitor of the above-mentioned [2], whereinring C is a pyrrole ring, an imidazole ring, a thiazole ring or apyrazole ring,[5] the acid secretion inhibitor of the above-mentioned [2], whereinring D is a benzene ring, a pyridine ring or a pyrimidine ring,[6] the acid secretion inhibitor of the above-mentioned [1], which is aproton pump inhibitor,[7] the acid secretion inhibitor of the above-mentioned [1], which is apotassium-competitive acid blocker,[8] the acid secretion inhibitor of the above-mentioned [1], which is anagent for the prophylaxis or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis, symptomaticgastroesophageal reflux disease (symptomatic GERD), Barrett's esophagus,functional dyspepsia, gastric cancer, stomach MALT lymphoma or gastrichyperacidity; or an inhibitor of upper gastrointestinal hemorrhage dueto peptic ulcer, acute stress ulcer, hemorrhagic gastritis or invasivestress,[9] a compound represented by the formula

wherein ring C is a saturated or unsaturated 5-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, ring D is a saturated or unsaturated 6-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, R^(1a) and R^(1b) are each an optionally substituted arylgroup or an optionally substituted heteroaryl group, R^(2a) and R^(2b)are each an optionally substituted alkyl group, an optionallysubstituted aryl group or an optionally substituted heteroaryl group,R^(6a), R^(7a), R^(6b) and R^(7b) are each absent, or a hydrogen atom, alower alkyl group, a halogen atom or a cyano group, R^(3a) and R^(3b)are each an aminomethyl group optionally substituted by 1 or 2 loweralkyl groups, R^(8b) is absent, or a hydrogen atom, a lower alkyl group,a halogen atom, a cyano group or an oxo group, excluding a compoundrepresented by the formula

wherein each symbol is as defined above, or a salt thereof,[10] the compound of the above-mentioned [9], which is represented bythe formula (Ia-5)

wherein R^(1a) is a C₆₋₁₄ aryl group or a 5- or 6-membered aromaticheterocyclic group or a fused ring group thereof, which is optionallysubstituted by substituent(s) selected from (i) halogen, (ii) hydroxy,(iii) cyano, (iv) C₁₋₆ alkyl optionally substituted by halogen, (v) C₁₋₆alkoxy optionally substituted by halogen, (vi) an amino group optionallysubstituted by C₁₋₆ alkyl, (vii) oxo, (viii) carbamoyl, (ix) mono-C₁₋₆alkyl-carbamoyl, (x) alkyl-carbamoyl, (xi) C₁₋₆ alkylsulfonyl and (xii)C₁₋₆ alkyl-carbonylamino, R^(2a) is an optionally substituted alkylgroup, an optionally substituted aryl group or an optionally substitutedheteroaryl group, R^(3a) is an aminomethyl group optionally substitutedby 1 or 2 lower alkyl groups, and R^(6a) is a hydrogen atom, a loweralkyl group, a halogen atom or a cyano group,[11] a prodrug of the compound of the above-mentioned [9],[12] a pharmaceutical agent comprising the compound of theabove-mentioned [9] or a prodrug thereof,[13] a method of treating or preventing peptic ulcer, Zollinger-Ellisonsyndrome, gastritis, reflux esophagitis, symptomatic gastroesophagealreflux disease (symptomatic GERD), Barrett's esophagus, functionaldyspepsia, gastric cancer, stomach MALT lymphoma or gastrichyperacidity; or a method of inhibiting upper gastrointestinalhemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagicgastritis or invasive stress, which comprises administering an effectiveamount of the compound of the above-mentioned [9] or a prodrug thereofto a mammal, and[14] use of the compound of the above-mentioned [9] or a prodrug thereoffor the production of an agent for the prophylaxis or treatment ofpeptic ulcer, Zollinger-Ellison syndrome, gastritis, reflux esophagitis,symptomatic gastroesophageal reflux disease (symptomatic GERD),Barrett's esophagus, functional dyspepsia, gastric cancer, stomach MALTlymphoma or gastric hyperacidity; or an inhibitor of uppergastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer,hemorrhagic gastritis or invasive stress.

In addition, the present invention relates to

[15] a proton pump inhibitor comprising a compound represented by theformula (I)

wherein ring A is a saturated or unsaturated 5- or 6-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, ring-constituting atoms X₁ and X₂ are each a carbon atom ora nitrogen atom, a ring-constituting atom X₃ is a carbon atom, anitrogen atom, an oxygen atom or a sulfur atom, R¹ is an optionallysubstituted aryl group or an optionally substituted heteroaryl group, R²is an optionally substituted alkyl group, an optionally substituted arylgroup or an optionally substituted heteroaryl group, R³ is anaminomethyl group optionally substituted by 1 or 2 lower alkyl groups,which is a substituent on a ring-constituting atom other than X₁, X₂ andX₃, ring A optionally further has substituent(s) selected from a loweralkyl group, a halogen atom, a cyano group and an oxo group, excluding acompound represented by the formula

wherein each symbol is as defined above, and a pyrrole ring optionallyfurther has substituent(s) selected from a lower alkyl group, a halogenatom, a cyano group and an oxo group, or a salt thereof, or a prodrugthereof,[16] the inhibitor of the above-mentioned [15], wherein the compoundrepresented by the formula (I) is a compound represented by the formula

wherein ring C is a saturated or unsaturated 5-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, ring D is a saturated or unsaturated 6-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, R^(1a) and R^(1b) are each an optionally substituted arylgroup or an optionally substituted heteroaryl group, R^(2a) and R^(2b)are each an optionally substituted alkyl group, an optionallysubstituted aryl group or an optionally substituted heteroaryl group,R^(6a), R^(7a), R^(6b) and R^(7b) are each absent, or a hydrogen atom, alower alkyl group, a halogen atom or a cyano group, R^(3a) and R^(3b)are each an aminomethyl group optionally substituted by 1 or 2 loweralkyl groups, and R^(8b) is absent, or a hydrogen atom, a lower alkylgroup, a halogen atom, a cyano group or an oxo group, excluding acompound represented by the formula

wherein each symbol is as defined above,[17] the inhibitor of the above-mentioned [16], wherein the compound isa compound represented by the formula (Ia),[18] the inhibitor of the above-mentioned [16], wherein ring C is apyrrole ring, an imidazole ring or a thiazole ring,[19] the inhibitor of the above-mentioned [16], wherein ring D is abenzene ring, a pyridine ring or a pyrimidine ring,[20] an agent for the treatment or prophylaxis of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis, SymptomaticGastroesophageal Reflux Disease (Symptomatic GERD), NUD (Non UlcerDyspepsia), gastric cancer, stomach MALT lymphoma, ulcer caused by anon-steroidal anti-inflammatory agent or hyperacidity or ulcer due topostoperative stress; or an inhibitor of upper gastrointestinalhemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagicgastritis or invasive stress, comprising a proton pump inhibitor of theabove-mentioned [15],[21] a compound represented by the formula

wherein ring C is a saturated or unsaturated 5-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, ring D is a saturated or unsaturated 6-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, R^(1a) and R^(1b) are each an optionally substituted arylgroup or an optionally substituted heteroaryl group, R^(2a) and R^(2b)are each an optionally substituted alkyl group, an optionallysubstituted aryl group or an optionally substituted heteroaryl group,R^(6a), R^(7a), R^(6b) and R^(7b) are each absent, or a hydrogen atom, alower alkyl group, a halogen atom or a cyano group, R^(3a) and R^(3b)are each an aminomethyl group optionally substituted by 1 or 2 loweralkyl groups, and R^(8b) is absent, or a hydrogen atom, a lower alkylgroup, a halogen atom, a cyano group or an oxo group, excluding acompound represented by the formula

wherein each symbol is as defined above, or a salt thereof,[22] a prodrug of the compound of the above-mentioned [21],[23] a pharmaceutical agent comprising the compound of theabove-mentioned [21] or a prodrug thereof,[24] a pharmaceutical agent of the above-mentioned [23], which is anagent for the prophylaxis or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis, symptomaticgastroesophageal reflux disease (symptomatic GERD), NUD (Non UlcerDyspepsia), gastric cancer, stomach MALT lymphoma, ulcer caused bynon-steroidal anti-inflammatory agent or gastric hyperacidity or ulcerdue to postoperative stress; or an inhibitor of upper gastrointestinalhemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagicgastritis or invasive stress,[25] a method for the prophylaxis or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis, symptomaticgastroesophageal reflux disease (symptomatic GERD), NUD (Non UlcerDyspepsia), gastric cancer, stomach MALT lymphoma, ulcer caused bynon-steroidal anti-inflammatory agent or gastric hyperacidity or ulcerdue to postoperative stress; or a method of inhibiting uppergastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer,hemorrhagic gastritis or invasive stress, comprising administering aneffective amount of the compound of the above-mentioned [21] or aprodrug thereof to mammal, and[26] use of the compound of the above-mentioned [21] or a prodrugthereof for the production of an agent for the prophylaxis or treatmentof peptic ulcer, Zollinger-Ellison syndrome, gastritis, refluxesophagitis, symptomatic gastroesophageal reflux disease (symptomaticGERD), NUD (Non Ulcer Dyspepsia), gastric cancer, stomach MALT lymphoma,ulcer caused by non-steroidal anti-inflammatory agent or gastrichyperacidity or ulcer due to postoperative stress; or an inhibitor ofupper gastrointestinal hemorrhage due to peptic ulcer, acute stressulcer, hemorrhagic gastritis or invasive stress.

Effect of the Invention

Compound (I) shows a superior proton pump inhibitory action.Conventional proton pump inhibitors such as omeprazole, lansoprazole andthe like form a covalent bond with a cysteine residue of H⁺/K⁺-ATPase,and irreversibly inhibit the enzyme activity. In contrast, compound (I)inhibits proton pump (H⁺/K⁺-ATPase) activity in a reversible and K⁺antagonist-like inhibitory manner, and consequently suppresses acidsecretion. Therefore, it is sometimes called a potassium-competitiveacid blocker (P-CAB), or an acid pump antagonist (APA). Compound (I)rapidly expresses the action and shows the maximum efficacy from theinitial administration. Furthermore, it characteristically shows lessinfluence of metabolic polymorphism (variation between patients) andlong duration of action. Accordingly, the present invention can providea clinically useful agent for the prophylaxis or treatment of pepticulcer (e.g., gastric ulcer, duodenal ulcer, anastomotic ulcer, ulcercaused by non-steroidal anti-inflammatory agent, ulcer due topostoperative stress etc.), Zollinger-Ellison syndrome, gastritis,erosive esophagitis, reflux esophagitis, symptomatic gastroesophagealreflux disease (Symptomatic GERD), Barrett's esophagus, functionaldyspepsia including NUD (Non Ulcer Dyspepsia), gastric cancer, stomachMALT lymphoma or hyperacidity; or a suppressant of uppergastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer,hemorrhagic gastritis or invasive stress; and the like. Since compound(I) shows low toxicity and is superior in water-solubility, in vivokinetics and efficacy expression, it is useful as a pharmaceuticalcomposition. Furthermore, since compound (I) is stable even under acidicconditions, it can be administered orally as a conventional tablet andthe like without formulating into an enteric-coated preparation. Thishas an advantageous consequence that the preparation (tablet and thelike) can be made smaller, and can be easily swallowed by patientshaving difficulty in swallowing, particularly the elderly and children.In addition, since it is free of a sustained release effect afforded byenteric-coated preparations, a gastric acid secretion-suppressive actionis expressed rapidly, and symptoms such as pain and the like can bealleviated rapidly.

In the formula (I), ring A is a saturated or unsaturated 5- or6-membered ring group optionally having, as a ring-constituting atombesides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom,an oxygen atom and a sulfur atom. Specific examples of ring A include5-membered ring groups such as a thiophene ring, a furan ring, a pyrrolering, an imidazole ring, a pyrazole ring, an isothiazole ring, athiazole ring, an isoxazole ring, an oxazole ring, a pyrrolidine ring, apyrroline ring, an imidazolidine ring, an imidazoline ring, apyrazolidine ring, a pyrazoline ring, a furazan ring, an oxadiazole ring(e.g., 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,3,4-oxadiazolering), a thiadiazole ring (e.g., 1,2,3-thiadiazole ring,1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring), a triazole ring (e.g.,1,2,3-triazole ring, 1,2,4-triazole ring), a tetrazole ring, atetrahydrofuran ring, a cyclopentane ring, a cyclopentene ring, acyclopentadiene ring and the like; and 6-membered ring groups such as apyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring, apiperidine ring, a piperazine ring, a morpholine ring, a thiomorpholinering, a pyran ring, a thiopyran ring, a triazine ring (e.g.,1,2,4-triazine ring, 1,3,5-triazine ring), an oxazine ring (e.g.,1,4-oxazine ring, 1,3-oxazine ring), a thiazine ring (e.g., 1,4-thiazinering, 1,3-thiazine ring), an oxadiazine ring, a thiadiazine ring, atetrahydropyran ring, a tetrahydropyridine ring (e.g.,1,2,3,6-tetrahydropyridine ring), a dihydropyridine ring (e.g.,1,4-dihydropyridine ring), a cyclohexane ring, a cyclohexene ring, acyclohexadiene ring, a benzene ring and the like.

Here, the ring-constituting atom (X₁) of ring A, to which a grouprepresented by —SO₂—R¹ is bonded and the ring-constituting atom (X₂) ofring A, to which a substituent represented by R² is bonded is a carbonatom or a nitrogen atom.

The ring-constituting atom (X₃) adjacent to X₁ is a carbon atom, anitrogen atom, an oxygen atom or a sulfur atom. When X₃ is a carbon atomor a nitrogen atom, a substituent (R⁶) selected from a lower alkylgroup, a halogen atom and a cyano group may be present at X₃. Examplesof the “lower alkyl group” for R⁶ include a C₁₋₄ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyletc. and the like.

Examples of the “halogen atom” for R⁶ include a fluorine atom, achlorine atom, a bromine atom and an iodine atom.

Examples of the aryl group in the “optionally substituted aryl group”for R¹ include a C₆₋₁₄ aryl group such as phenyl, 1-naphthyl,2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and thelike.

Examples of the substituent of the aryl group include (1) a halogen atom(e.g., fluorine atom, chlorine atom, bromine atom, iodine atom etc.),(2) nitro, (3) cyano, (4) hydroxy, (5) C₁₋₆ alkoxy optionally having 1to 5 (preferably 1 to 3) halogen atoms (e.g., fluorine, chlorine,bromine, iodine) (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy etc.), (6)C₆₋₁₄ aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7) C₇₋₁₆ aralkyloxy(e.g., benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy,2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy,4-phenylbutyloxy, 5-phenylpentyloxy etc.), (8) mercapto, (9) C₁₋₆alkylthio optionally having 1 to 5 (preferably 1 to 3) halogen atoms(e.g., fluorine, chlorine, bromine, iodine) (e.g., methylthio,difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio,hexylthio etc.), (10) C₆₋₁₄ arylthio (e.g., phenylthio, naphthylthioetc.), (11) C₇₋₁₆ aralkylthio (e.g., benzylthio, phenethylthio,diphenylmethylthio, 1-naphthylmethylthio, 2-naphthylmethylthio,2,2-diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio,5-phenylpentylthio etc.), (12) amino, (13) mono-C₁₋₆ alkylamino (e.g.,methylamino, ethylamino etc.), (14) mono-C₆₋₁₄ arylamino (e.g.,phenylamino, 1-naphthylamino, 2-naphthylamino etc.), (15) mono-C₇₋₁₆aralkylamino (e.g., benzylamino etc.), (16) di-C₁₋₆ alkylamino (e.g.,dimethylamino, diethylamino etc.), (17) di-C₆₋₁₄ arylamino (e.g.,diphenylamino etc.), (18) di-C₇₋₁₆ aralkylamino (e.g., dibenzylaminoetc.), (19) formyl, (20) C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyletc.), (21) C₆₋₁₄ aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyletc.), (22) carboxyl, (23) C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.), (24) C₆₋₁₄aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), (25) carbamoyl, (26)thiocarbamoyl, (27) mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl,ethylcarbamoyl), (28) di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl,diethylcarbamoyl, ethylmethylcarbamoyl etc.), (29) C₆₋₁₄ aryl-carbamoyl(e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.),(30) C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (31)C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl etc.), (32) C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl,ethylsulfinyl etc.), (33) C₆₋₁₄ arylsulfinyl (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl etc.), (34) formylamino, (35)C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.), (36) C₆₋₁₄aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37) C₁₋₆alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, butoxycarbonylamino etc.), (38) C₁₋₆alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino etc.),(39) C₆₋₁₄ arylsulfonylamino (e.g., phenylsulfonylamino,2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), (40) C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), (41) C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy etc.), (42) C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy etc.), (43) mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.),(44) di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy etc.), (45) C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to 7-memberedsaturated cyclic amino optionally containing, besides one nitrogen atomand carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom (e.g., pyrrolidin-1-yl,piperidino, piperazin-1-yl, morpholino, thiomorpholino,hexahydroazepin-1-yl etc.), (47) a 5- to 10-membered aromaticheterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.), (48) C₁₋₃alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), (49) C₃₋₇cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl etc.), (50) a C₁₋₆ alkyl group optionally having 1 to 5(preferably 1 to 3) halogen atoms (e.g., fluorine, chlorine, bromine,iodine) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl,n-hexyl, isohexyl etc.), (51) a C₂₋₆ alkenyl group (e.g., allyl,isopropenyl, isobutenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl etc.)optionally having 1 to 5 (preferably 1 to 3) halogen atoms (e.g.,fluorine, chlorine, bromine, iodine), (52) a C₂₋₆ alkynyl group (e.g.,propargyl, 2-butynyl, 3-butynyl, 3-pentynyl, 3-hexynyl etc.), (53) aC₆₋₁₄ aryl group (e.g., phenyl etc.) optionally having 1 to 5(preferably 1 to 3) halogen atoms (e.g., fluorine, chlorine, bromine,iodine), (54) C₇₋₁₆ aralkyl (e.g., benzyl, phenethyl etc.) optionallyhaving 1 to 5 (preferably 1 to 3) halogen atoms (e.g., fluorine,chlorine, bromine, iodine), (55) oxo, and the like.

The substituent may be present at a substitutable position, and thenumber of the substituents is 1 to 5, preferably 1 to 3.

Examples of the heteroaryl group in the “optionally substitutedheteroaryl group” for R¹ include a 5- or 6-membered aromaticheterocyclic group or a fused ring group thereof such as pyrrolyl (e.g.,1-, 2- or 3-pyrrolyl), pyrazolyl (e.g., 1-, 3-, 4- or 5-pyrazolyl),imidazolyl (e.g., 1-, 2-, 4- or 5-imidazolyl), triazolyl (e.g.,1,2,3-triazol-4-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-5-yl,1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl,1,2,4-triazol-5-yl), tetrazolyl (e.g., tetrazol-1-, 2- or 5-yl), furyl(e.g., 2- or 3-furyl), thienyl (e.g., 2- or 3-thienyl), oxazolyl (e.g.,2-, 4- or 5-oxazolyl), isoxazolyl (e.g., 3-, 4- or 5-isoxazolyl),oxadiazolyl (e.g., 1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl), triazolyl (e.g., 2-,4- or 5-thiazolyl), isothiazolyl (e.g., 3-, 4- or 5-isothiazolyl),thiadiazolyl (e.g., 1,2,3-thiadiazol-4- or 5-yl, 1,2,4-thiadiazol-3- or5-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl), pyridyl (e.g., 2-,3- or 4-pyridyl), pyridazinyl (e.g., 3- or 4-pyridazinyl), pyrimidinyl(e.g., 2-, 4- or 5-pyrimidinyl), pyrazinyl, benzofuryl (e.g., 2- or3-benzofuryl), benzothienyl (e.g., 2- or 3-benzothienyl), isoindolyl(e.g., 1- or 3-isoindolyl), benzimidazolyl (e.g., 2-benzimidazolyl),benzoxazolyl (e.g., 2-benzoxazolyl), benzisoxazolyl (e.g.,3-benzisoxazolyl), benzothiazolyl (e.g., 2-benzothiazolyl),benzisothiazolyl (e.g., 3-benzisothiazolyl), cinnolinyl (e.g., 3- or4-cinnolinyl), quinazolinyl (e.g., 2- or 4-quinazolinyl), quinoxalinyl(e.g., 2- or 3-quinoxalinyl), phthalazinyl (e.g., 1- or 4-phthalazinyl),pteridinyl, indolyl (e.g., 3H-indol-2-, 3-, 4-, 5-, 6- or 7-yl),quinolyl (e.g., 3-, 4-, 5-, 6-, 7- or 8-quinolyl), isoquinolyl (e.g.,1-, 3- or 4-isoquinolyl), pyrido[2,3-d]pyrimidinyl (e.g.,pyrido[2,3-d]pyrimidin-2-yl), naphthyridinyl such as 1,5-, 1,6-, 1,7-,1,8-, 2,6- or 2,7-naphthyridinyl and the like (e.g., 1,5-naphthyridin-2-or 3-yl), thieno[2,3-d]pyridyl (e.g., thieno[2,3-d]pyridin-3-yl),pyrazinoquinolyl (e.g., pyrazino[2,3-d]quinolin-2-yl),imidazo[1,2-a]pyridyl, imidazo[2,1-b]thiazolyl,imidazo[1,2-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]imidazolyl, imidazo[2,1-b](1.3.4)thiadiazolyl,pyrazolo[1,5-a]pyrimidinyl, pyrazolo[5,1-b]thiazolyl orpyrazolo[1,5-a]pyridyl and the like.

Examples of the substituent of the heteroaryl group include thosesimilar to the substituents which the aforementioned aryl group in R¹optionally has. The substituent may be present at a substitutableposition, and the number of the substituents is 1 to 5, preferably 1 to3.

Examples of the alkyl group of the “optionally substituted alkyl group”for R² include a C₁₋₆ alkyl group such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like.

Examples of the substituent of the alkyl group include (1) a halogenatom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atometc.), (2) nitro, (3) cyano, (4) hydroxy, (5) C₁₋₆ alkoxy optionallyhaving 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine)(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy etc.), (6) C₆₋₁₄ aryloxy(e.g., phenyloxy, naphthyloxy etc.), (7) C₇₋₁₆ aralkyloxy (e.g.,benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy,2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy,4-phenylbutyloxy, 5-phenylpentyloxy etc.), (8) mercapto, (9) C₁₋₆alkylthio optionally having 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine, iodine) (e.g., methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio etc.), (10) C₆₋₁₄arylthio (e.g., phenylthio, naphthylthio etc.), (11) C₇₋₁₆ aralkylthio(e.g., benzylthio, phenethylthio, diphenylmethylthio,1-naphthylmethylthio, 2-naphthylmethylthio, 2,2-diphenylethylthio,3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio etc.) (12)amino, (13) mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino etc.),(14) mono-C₆₋₁₄ arylamino (e.g., phenylamino, 1-naphthylamino,2-naphthylamino etc.), (15) mono-C₇₋₁₆ aralkylamino (e.g., benzylaminoetc.), (16) di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino etc.),(17) di-C₆₋₁₄ arylamino (e.g., diphenylamino etc.), (18) di-C₇₋₁₆aralkylamino (e.g., dibenzylamino etc.), (19) formyl, (20) C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl etc.), (21) C₆₋₁₄ aryl-carbonyl(e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), (22) carboxyl, (23) C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl etc.), (24) C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl etc.), (25) carbamoyl, (26) thiocarbamoyl, (27)mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.),(28) di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl etc.), (29) C₆₋₁₄ aryl-carbamoyl (e.g.,phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), (30)C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (31)C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl etc.), (32) C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl,ethylsulfinyl etc.), (33) C₆₋₁₄ arylsulfinyl (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl etc.), (34) formylamino, (35)C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.), (36) C₆₋₁₄aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37) C₁₋₆alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, butoxycarbonylamino etc.), (38) C₁₋₆alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino etc.),(39) C₆₋₁₄ arylsulfonylamino (e.g., phenylsulfonylamino,2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), (40) C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), (41) C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy etc.), (42) C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy etc.), (43) mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.),(44) di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy etc.), (45) C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to 7-memberedsaturated cyclic amino optionally containing, besides one nitrogen atomand carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom (e.g., pyrrolidin-1-yl,piperidino, piperazin-1-yl, morpholino, thiomorpholino,hexahydroazepin-1-yl etc.), (47) a 5- to 10-membered aromaticheterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.), (48) C₁₋₃alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), (49) C₃₋₇cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl etc.) and the like.

The number of the substituents is 1 to 3.

Examples of the “optionally substituted aryl group” or “optionallysubstituted heteroaryl group” for R² include those similar to theaforementioned “optionally substituted aryl group” and “optionallysubstituted heteroaryl group” for R¹.

R³ is a substituent on a ring-constituting atom other than X₁, X₂ andX₃, and is an aminomethyl group optionally substituted by 1 or 2 loweralkyl groups (—CH₂—NR⁴R⁵).

Examples of the lower alkyl group of the “aminomethyl group optionallysubstituted by 1 or 2 lower alkyl groups” include a C₁₋₄ alkyl groupsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl etc. and the like.

That is, R⁴ and R⁵ in —CH₂—NR⁴R⁵ for R³ are the same or different andeach is a hydrogen atom or a lower alkyl group such as a C₁₋₄ alkylgroup and the like.

Preferred as R³ is, from those mentioned above, an aminomethyl group(—CH₂—NH₂), a methylaminomethyl group (—CH₂—NH(CH₃)) and adimethylaminomethyl group (—CH₂—N(CH₃)₂).

Ring A may further have substituent(s), besides the substituentrepresented by —SO₂—R¹, R² and R³, at substitutable position(s).Preferred as the substituent are a lower alkyl group (e.g., C₁₋₄ alkylgroup such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl etc. and the like), a halogen atom (e.g., fluorineatom, chlorine atom, bromine atom, iodine atom), a cyano group and anoxo group. The number of the substituents is 1 to 3, preferably 1 or 2.

A compound represented by the formula (I) is specifically a compoundrepresented by the formula (I′)

wherein ring B is a saturated or unsaturated 5- or 6-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, ring-constituting atoms X₁ and X₂ are each a carbon atom ora nitrogen atom, ring-constituting atoms X₃ and X₄ are each a carbonatom, a nitrogen atom, an oxygen atom or a sulfur atom, when X₃ or X₄ isa carbon atom or a nitrogen atom, each may have substituent(s) selectedfrom a lower alkyl group, a halogen atom and a cyano group, X₅ is (1) acarbon atom or a nitrogen atom, said carbon atom or nitrogen atom havingsubstituent R³ thereon, or (2) —X₆-X₇— (wherein X₆ and X₇ are each acarbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, at leastone of X₆ and X₇ is a carbon atom or a nitrogen atom, having asubstituent R³ on its atom, and the other is any of a carbon atom, anitrogen atom, an oxygen atom and a sulfur atom, when it is a carbonatom or a nitrogen atom, it may have a substituent (R⁸) selected from alower alkyl group, a halogen atom and a cyano group, and when it is acarbon atom, it is optionally substituted by oxo), R¹ is an optionallysubstituted aryl group or an optionally substituted heteroaryl group, R²is an optionally substituted alkyl group, an optionally substituted arylgroup or an optionally substituted heteroaryl group, and R³ isaminomethyl (—CH₂—NR⁴R⁵) group (R⁴ and R⁵ are the same or different andeach is a hydrogen atom or a lower alkyl group such as a C₁₋₄ alkylgroup (e.g., methyl, ethyl) and the like) optionally substituted by 1 or2 lower alkyl groups, excluding a compound represented by the formula

wherein each symbol is as defined above, and a pyrrole ring isoptionally further substituted by a substituent selected from a loweralkyl group, a halogen atom and a cyano group, or a salt thereof[hereinafter to be abbreviated as compound (I′)].

In compound (I′), examples of the “saturated or unsaturated 5- or6-membered ring group optionally having, as a ring-constituting atombesides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom,an oxygen atom and a sulfur atom” for ring B include those similar tothe 5- or 6-membered ring groups exemplified for ring A.

The ring-constituting atoms X₁ and X₂ are each a carbon atom or anitrogen atom, and the ring-constituting atoms X₃ and X₄ are each acarbon atom, a nitrogen atom, an oxygen atom or a sulfur atom.

When X₃ is a carbon atom or a nitrogen atom, a substituent (R⁶) selectedfrom a lower alkyl group, a halogen atom and a cyano group may bepresent on X₃.

Specific examples of R⁶ include those similar to those exemplified forthe aforementioned compound (I).

When X₄ is a carbon atom or a nitrogen atom, a substituent (R⁷) selectedfrom a lower alkyl group, a halogen atom and a cyano group may bepresent on X₄.

Specific examples of the “lower alkyl group” and “halogen atom” for R⁷include those similar to R⁶.

In addition, specific examples of the above-mentioned “lower alkylgroup” and “halogen atom” for R⁸ include those similar to R⁶.

In compound (I′), examples of the R¹, R² and R³ include those similar tothose exemplified for R¹, R² and R³ of compound (I).

Preferable embodiments of compounds (I) and (I′) are the followingcompounds (Ia) and (Ib).

A compound represented by the formula

wherein ring C is a saturated or unsaturated 5-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, ring D is a saturated or unsaturated 6-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, R^(1a) and R^(1b) are each an optionally substituted arylgroup or an optionally substituted heteroaryl group, R^(2a) and R^(2b)are each an optionally substituted alkyl group, an optionallysubstituted aryl group or an optionally substituted heteroaryl group,R^(6a), R^(7a), R^(6b) and R^(7b) are each absent, or a hydrogen atom, alower alkyl group, a halogen atom or a cyano group, R^(3a) and R^(3b)are each an aminomethyl group optionally substituted by 1 or 2 loweralkyl groups, and R^(8b) is absent or a hydrogen atom, a lower alkylgroup, a halogen atom, a cyano group or an oxo group, excluding acompound represented by the formula

wherein each symbol is as defined above, or a salt thereof.

In compound (Ia), specific examples of ring C include 5-membered ringgroups such as a thiophene ring, a furan ring, a pyrrole ring, animidazole ring, a pyrazole ring, an isothiazole ring, a thiazole ring,an isoxazole ring, an oxazole ring, a pyrrolidine ring, a pyrrolinering, an imidazolidine ring, an imidazoline ring, a pyrazolidine ring, apyrazoline ring, a furazan ring, an oxadiazole ring (e.g.,1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,3,4-oxadiazole ring), athiadiazole ring (e.g., 1,2,3-thiadiazole ring, 1,2,4-thiadiazole ring,1,3,4-thiadiazole ring), a triazole ring (e.g., 1,2,3-triazole ring,1,2,4-triazole ring), a tetrazole ring, a tetrahydrofuran ring, acyclopentane ring, a cyclopentene ring, a cyclopentadiene ring and thelike. Preferred are a pyrrole ring, an imidazole ring and a thiazolering.

Here, the ring-constituting atom of ring C to which a group representedby —SO₂—R^(1a) is bonded, the ring-constituting atom of ring C to whicha substituent for R^(2a) is bonded and the ring-constituting atom ofring C to which a substituent for R^(3a) is bonded are each a carbonatom or a nitrogen atom.

The ring-constituting atom of ring C to which a substituent for R^(6a)or R^(7a) is bonded is a carbon atom, a nitrogen atom, an oxygen atom ora sulfur atom. When the ring-constituting atom of ring C to which asubstituent for R^(6a) or R^(7a) is bonded is an oxygen atom or a sulfuratom, a substituent for R^(6a) or R^(7a) cannot be present, which meansthat these substituents are void. On the other hand, when thering-constituting atom of ring C to which a substituent for R^(6a) orR^(7a) is bonded is a carbon atom or a nitrogen atom, R^(6a) and R^(7a)are each absent, or a hydrogen atom, a lower alkyl group, a halogen atomor a cyano group.

When the ring-constituting atom of ring C to which a substituent forR^(6a) or R^(7a) is bonded is a carbon atom or a nitrogen atom, acompound wherein R^(6a) or R^(7a) is absent is a compound wherein thering-constituting atom of ring C to which a substituent for R^(6a) orR^(7a) is bonded is a nitrogen atom and a double bond is present betweenthe nitrogen atom and a ring-constituting atom adjacent to the nitrogenatom.

Examples of the “lower alkyl group” for R^(6a) or R^(7a) include C₁₋₄alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl etc. and the like.

Examples of the “halogen atom” for R^(6a) or R^(7a) include a fluorineatom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the R^(1a), R^(2a) and R^(3a) include those similar to theabove-mentioned groups exemplified for R¹, R² and R³, respectively.

In compound (Ib), specific examples of ring D include 6-membered ringgroups such as a pyridine ring, a pyrazine ring, a pyrimidine ring, apyridazine ring, a piperidine ring, a piperazine ring, a morpholinering, a thiomorpholine ring, a pyran ring, a thiopyran ring, a triazinering (e.g., 1,2,4-triazine ring, 1,3,5-triazine ring), an oxazine ring(e.g., 1,4-oxazine ring, 1,3-oxazine ring), a thiazine ring (e.g.,1,4-thiazine ring, 1,3-thiazine ring), an oxadiazine ring, a thiadiazinering, a tetrahydropyran ring, a tetrahydropyridine ring (e.g.,1,2,3,6-tetrahydropyridine ring), a dihydropyridine ring (e.g.,1,4-dihydropyridine ring), a cyclohexane ring, a cyclohexene ring, acyclohexadiene ring, a benzene ring and the like. Preferred are abenzene ring, a pyridine ring and a pyrimidine ring.

Here, the ring-constituting atom of ring D to which a group representedby —SO₂—R^(1b) is bonded, the ring-constituting atom of ring D to whicha substituent for R^(2b) is bonded and the ring-constituting atom ofring D to which a substituent for R^(3b) is bonded are each a carbonatom or a nitrogen atom.

The ring-constituting atom of ring D to which a substituent for R^(6b),R^(7b) or R^(8b) is bonded is a carbon atom, a nitrogen atom, an oxygenatom or a sulfur atom. When the ring-constituting atom of ring D towhich a substituent for R^(6b), R^(7b) or R^(8b) is bonded is an oxygenatom or a sulfur atom, a substituent for R^(6b), R^(7b) or R^(8b) cannotbe present, which means that these substituents are void. On the otherhand, when the ring-constituting atom of ring D to which a substituentfor R^(6b), R^(7b) or R^(8b) is bonded is a carbon atom or a nitrogenatom, R^(6b), R^(7b) or R^(8b) are each absent, or a hydrogen atom, alower alkyl group, a halogen atom or a cyano group.

A compound wherein R^(6b), R^(7b) or R^(8b) is absent is a compoundwherein the ring-constituting atom of ring D to which a substituent forR^(6b), R^(7b) or R^(8b) is bonded is a nitrogen atom and a double bondis present between the nitrogen atom and a ring-constituting atomadjacent to the nitrogen atom.

Examples of the “lower alkyl group” and “halogen atom” for R^(6b),R^(7b) or R^(8b) include those similar to the above-mentioned “loweralkyl group” and “halogen atom” for R^(6a) or R^(7a).

Examples of the R^(1b), R^(2b) and R^(3b) include those similar to theabove-mentioned groups exemplified for R¹, R² and R³, respectively.

Preferable specific examples of compound (Ia) having a 5-membered ringstructure are shown below.

Each symbol in the formulas of the above-mentioned compounds(Ia-1)-(Ia-36) is as defined above.

Of the above, preferred are pyrrole ring, imidazole ring and thiazolering derivatives represented by compounds (Ia-1)-(Ia-12) and(Ia-21)-(Ia-24).

Preferable specific examples of compound (Ib) having a 6-membered ringstructure are shown below.

Each symbol in the formulas of the above-mentioned compounds(Ib-1)-(Ib-41) is as defined above.

Of the above, preferred are benzene ring, pyridine ring and pyrimidinering derivatives represented by compounds (Ib-1)-(Ib-28).

In the above-mentioned compounds (I), (I′), (Ia), (Ib), (Ia-1)-(Ia-36)and (Ib-1)-(Ib-41), preferred as R¹, R^(1a), R^(1b) is a C₆₋₁₄ arylgroup or a 5- or 6-membered aromatic heterocyclic group or a fused ringgroup thereof (e.g., a fused ring group of 5- or 6-membered aromaticheterocyclic group and a benzene ring or a 5- or 6-membered aromaticheterocycle) (e.g., C₆₋₁₄ aryl group such as phenyl, 1- or 2-naphthyland the like; 5- or 6-membered aromatic heterocyclic group such as 2- or3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4-or 5-thiazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4-or 5-isothiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, 3- or 4-pyridazinyl, 2-pyrazinyl and the like; fused ringgroup such as 2- or 3-benzofuryl, 2- or 3-benzothienyl, 1- or3-isoindolyl, 2-benzimidazolyl, 2-benzooxazolyl, 3-benzoisoxazolyl,2-benzothiazolyl, 3-benzoisothiazolyl, 2-, 3- or 4-quinolyl, 1-, 3- or4-isoquinolyl, 3- or 4-cinnolinyl, 2- or 4-quinazolinyl, 2- or3-quinoxalinyl, 1- or 4-phthalazinyl, naphthyridinyl, pteridinyl etc.and the like), which are optionally substituted by 1 to 3 substituentsselected from (i) halogen (e.g., fluorine, chlorine, bromine, iodine),(ii) hydroxy, (iii) cyano, (iv) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine), (v) C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine), (vi) an aminogroup optionally substituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.),(vii) oxo, (viii) carbamoyl, (ix) mono-C₁₋₆ alkyl-carbamoyl (e.g.,methylcarbamoyl, ethylcarbamoyl etc.), (x) di-C₁₋₆ alkyl-carbamoyl(e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.),(xi) C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.) and(xii) C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.).

Among these, preferred is a phenyl group, a pyridyl group (e.g., 2-, 3-or 4-pyridyl) or a benzothienyl group (e.g., 2- or 3-benzothienyl), eachoptionally substituted by 1 to 3 substituents selected from (i) halogen(e.g., fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano,(iv) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxyetc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine), (vi) amino group optionallysubstituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.), (vii) oxo,(viii) carbamoyl, (ix) mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl,ethylcarbamoyl etc.), (x) di-C₁₋₆ alkyl-carbamoyl (e.g.,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), (xi)C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.) and (xii)C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.), particularlypreferably, a phenyl group or a pyridyl group each optionallysubstituted by 1 to 3 substituents selected from (i) halogen (e.g.,fluorine, chlorine, bromine, iodine), (ii) C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine) and (iii) C₁₋₆alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5(preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine).

In the above-mentioned compounds (I), (I′), (Ia), (Ib), (Ia-1)-(Ia-36)and (Ib-1)-(Ib-41), preferable examples of the R², R^(2a), R^(2b)include [1] a C₆₋₁₄ aryl group (e.g., phenyl group) optionallysubstituted by 1 to 5 (preferably 1 to 3) substituents selected from (i)halogen (e.g., fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii)cyano, (iv) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxyetc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine), (vi) amino group optionallysubstituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.), (vii)carbamoyl, (viii) mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl,ethylcarbamoyl etc.), (ix) di-C₁₋₆ alkyl-carbamoyl (e.g.,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), (x)C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.) and (xi)C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.), [2] a 5-6-memberedaromatic heterocyclic group or a fused ring group thereof (e.g., a fusedring group of a 5- or 6-membered aromatic heterocyclic group and abenzene ring or 5-6-membered aromatic heterocycle) (e.g., 5- or6-membered aromatic heterocyclic group such as 2- or 3-thienyl, 2- or3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl,2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or5-isothiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or5-pyrimidinyl, 3- or 4-pyridazinyl, 2-pyrazinyl and the like; fused ringgroup such as 2- or 3-benzofuryl, 2- or 3-benzothienyl, 1- or3-isoindolyl, 2-benzimidazolyl, 2-benzooxazolyl, 3-benzoisooxazolyl,2-benzothiazolyl, 3-benzoisothiazolyl, 2-, 3- or 4-quinolyl, 1-, 3- or4-isoquinolyl, 3- or 4-cinnolinyl, 2- or 4-quinazolinyl, 2- or3-quinoxalinyl, 1- or 4-phthalazinyl, naphthyridinyl, pteridinyl etc.and the like) optionally substituted by 1 to 3 substituents selectedfrom (i) halogen (e.g., fluorine, chlorine, bromine, iodine), (ii)hydroxy, (iii) cyano, (iv) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine), (v) C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine), (vi) amino groupoptionally substituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.),(vii) carbamoyl, (viii) mono-C₁₋₆ alkyl-carbamoyl (e.g.,methylcarbamoyl, ethylcarbamoyl etc.), (ix) di-C₁₋₆ alkyl-carbamoyl(e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.),(x) C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.) and(xi) C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.), [3] C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5(preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine, iodine)and the like.

Among these, [1] a C₆₋₁₄ aryl group (e.g., phenyl group) optionallysubstituted by 1 to 5 (preferably 1 to 3) substituents selected from (i)halogen (e.g., fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii)cyano, (iv) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxyetc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine), (vi) amino group optionallysubstituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.), (vii)carbamoyl, (viii) mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl,ethylcarbamoyl etc.), (ix) di-C₁₋₆ alkyl-carbamoyl (e.g.,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), (x)C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.) and (xi)C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.), [2] 2- or 3-thienylor 2-, 3- or 4-pyridyl optionally substituted by 1 to 3 substituentsselected from (i) halogen (e.g., fluorine, chlorine, bromine, iodine),(ii) hydroxy, (iii) cyano, (iv) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine), (v) C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine), (vi) amino groupoptionally substituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.),(vii) carbamoyl, (viii) mono-C₁₋₆ alkyl-carbamoyl (e.g.,methylcarbamoyl, ethylcarbamoyl etc.), (ix) di-C₁₋₆ alkyl-carbamoyl(e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.),(x) C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.) and(xi) C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.), or [3]C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5(preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine, iodine)and the like is preferable. Furthermore, [1] a phenyl group optionallysubstituted by 1 to 5 (preferably 1 to 3) substituents selected from (i)a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and (ii) C₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1to 5 (preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), or [2] C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5% (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) is preferable.

Particularly, preferred as R², R^(2a), R^(2b) is a phenyl group, a2-fluorophenyl group or a 2-methylphenyl group; and C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.).

In the above-mentioned compounds (I), (I′), (Ia), (Ib), (Ia-1)-(Ia-36)and (Ib-1)-(Ib-41), preferred as R³, R^(3a), R^(3b) are an aminomethylgroup (—CH₂—NH₂), a methylaminomethyl group (—CH₂—NH(CH₃)) and adimethylaminomethyl group (—CH₂—N(CH₃)₂). Particularly, an aminomethylgroup is preferable.

In the above-mentioned compounds (I), (I′), (Ia), (Ib), (Ia-1)-(Ia-36)and (Ib-1)-(Ib-41), preferred as R⁶, R^(6a), R^(6b) are [1] absent(e.g., compounds (Ia-7), (Ia-9), (Ia-14), (Ia-18)-(Ia-20),(Ia-22)-(Ia-24), (Ia-26), (Ia-28), (Ia-31), (Ia-32), (Ia-35), (Ia-36),(Ib-8), (Ib-15), (Ib-19), (Ib-20), (Ib-36), (Ib-37), (Ib-39), (Ib-41)etc.), [2] a hydrogen atom, [3] a C₁₋₄ alkyl group such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and thelike, [4] a halogen atom (e.g., fluorine, chlorine, bromine, iodine) and[5] a cyano group.

In the above-mentioned compounds (I′), (Ia), (Ib), (Ia-1)-(Ia-36) and(Ib-1)-(Ib-41), preferred as R⁷, R^(7a), R^(7b) are [1] absent (e.g.,compounds (Ia-5), (Ia-12), (Ia-16)-(Ia-18), (Ia-20)-(Ia-22), (Ia-24),(Ia-25), (Ia-27), (Ia-32), (Ia-36), (Ib-4), (Ib-11), (Ib-23), (Ib-24),(Ib-26), (Ib-28), (Ib-31), (Ib-33) etc.), [2] a hydrogen atom, [3] aC₁₋₄ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl and the like, [4] a halogen atom (e.g.,fluorine, chlorine, bromine, iodine) and [5] a cyano group.

In the above-mentioned compounds (I′), (Ib) and (Ib-1)-(Ib-41),preferred as R⁸, R^(8b) are [1] absent (e.g., compounds (Ib-6), (Ib-13),(Ib-18), (Ib-20), (Ib-22), (Ib-24), (Ib-32), (Ib-33), (Ib-35), (Ib-37)etc.), [2] an oxo group (e.g., compound (Ib-29)) or [3] a hydrogen atomand [4] a C₁₋₄ alkyl group such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl etc. and the like.

In the above-mentioned compounds (I), (I′), (Ia), (Ib), (Ia-1)-(Ia-36)and (Ib-1)-(Ib-41), preferable embodiments of each substituent mentionedabove can be freely combined.

As compound (I),N-methyl-1-[4-methyl-1-phenyl-5-(phenylsulfonyl)-1H-pyrrol-3-yl]methanamine,N,N-dimethyl-1-{1-[(4-methylphenyl)sulfonyl]-2-phenyl-1H-imidazol-4-yl}methanamine,1-{1-[(3-methoxyphenyl)sulfonyl]-2-phenyl-1H-imidazol-4-yl}-N-methylmethanamine,N-methyl-1-[4-phenyl-5-(phenylsulfonyl)-1,3-thiazol-2-yl]methanamine ora salt thereof is particularly preferable.

Examples of the salt of compound (I) include metal salt, ammonium salt,salts with organic bases, salts with inorganic acids, salts with organicacids, salts with basic or acidic amino acids and the like. Preferableexamples of metal salt include alkali metal salts such as sodium salt,potassium salt and the like; alkaline earth metal salts such as calciumsalt, magnesium salt, barium salt and the like; aluminum salt and thelike. Preferable examples of the salt with organic base include a saltwith trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine, N,N′-dibenzylethylenediamine and the like. Preferableexamples of the salt with inorganic acid include a salt withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like. Preferable examples of the salt withorganic acid include a salt with formic acid, acetic acid,trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like. Preferable examples of the salt with basic amino acid includea salt with arginine, lysin, ornithine and the like. Preferable examplesof the salt with acidic amino acid include a salt with aspartic acid,glutamic acid and the like.

Of these, pharmaceutically acceptable salts are preferable. For example,when a compound contains an acidic functional group, inorganic saltssuch as alkali metal salt (e.g., sodium salt, potassium salt etc.),alkaline earth metal salt (e.g., calcium salt, magnesium salt, bariumsalt etc.) and the like, ammonium salt and the like; and when a compoundcontains a basic functional group, for example, salts with inorganicacid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid and the like, or salts with organic acid such asacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid,maleic acid, citric acid, succinic acid, methanesulfonic acid,p-toluenesulfonic acid and the like can be mentioned.

The production methods of compound (I) in the present invention areexplained.

The compounds (II)-(XXI) in the formulas may form salts, and as suchsalts, for example, those similar to the salts of compound (I) can bementioned.

In the formulas, n is an integer of 0, 1 and 2. When n is 0 or 1, eachcompound can be converted to a compound wherein n is 2 by oxidation witha suitable oxidant.

While the compounds obtained in the respective steps can be used for thenext reaction in the form of a reaction mixture or a crude product, theycan also be easily isolated and purified from the reaction mixture by aknown separation and purification means, such as recrystallization,distillation, chromatography and the like.

Compound (II) wherein R² is as defined above, R⁹ is a C₁₋₄ alkyl groupsuch as methyl, ethyl, propyl, isopropyl or butyl and the like, L is ahydrogen atom or a leaving group such as halogen (e.g., fluorine,chlorine, bromine, iodine), methanesulfonyloxy, p-toluenesulfonyloxy andthe like may be a commercially available product, or can be producedaccording to a method known per se, for example, the methods describedin J.C.S. Chem. Commun., page 26 (1983), J. Heterocyclic. Chem, vol. 13,page 1145 (1976), WO04/7478 and J. Med. Chem., vol. 35, page 4195(1992), J. Org. Chem., vol. 39, page 1290 (1974) and the like, or amethod analogous thereto.

Compound (IV) wherein each symbol is as defined above can be produced byreacting compound (II) with a compound represented by the formula (III)

wherein each symbol is as defined above, X¹ is a hydrogen atom or aleaving group such as halogen (e.g., fluorine, chlorine, bromine,iodine) and the like.

This reaction is advantageously performed using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, hydrocarbons such as benzene, toluene and the like,ethers such as tetrahydrofuran and the like, amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like, and the likeor a mixed solvent thereof and the like are preferable.

Use of a base is effective for the reaction. As the base, for example,inorganic bases such as sodium hydride, sodium hydroxide, potassiumhydroxide and the like, basic salts such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydrogen carbonate and the like,metal bases such as potassium ethoxide, potassium tert-butoxide, sodiummethoxide, sodium ethoxide and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like, and the like canbe mentioned. The amount of the base to be used is about 1 to about 10mol, preferably about 1 to about 5 mol, per 1 mol of compound (II).

In addition, this reaction can be also performed in the co-presence ofcrown ether or a halogenating agent. Examples of the crown ether include15-crown-5-ether, 18-crown-6-ether and the like, and examples of thehalogenating agent include N-iodosuccinimide, N-bromosuccinimide,N-chlorosuccinimide, bromine and the like. The amount of these crownether and halogenating agent to be used is each about 1-about 10 mol,preferably about 1-about 5 mol, per 1 mol of compound (II).

While the reaction time varies depending on the reagents and solvents tobe used, it is generally about 30 min to about 24 hr, preferably about30 min to about 8 hr.

The reaction temperature is generally about 0° C. to about 100° C.,preferably about 10° C. to about 50° C.

In addition, this reaction can also be performed by a method similar toOrg. Lett., vol. 6, page 4587 (2004) and Synlett, page 1254 (2004) and amethod analogous thereto.

Compound (V) wherein each symbol in the formula is as defined above canbe produced by reducing compound (IV) with a reducing agent such aslithium aluminum hydride, diisobutyl aluminum hydride, sodiumborohydride, calcium borohydride and the like. As the reducing agent,diisobutyl aluminum hydride is particularly preferable. The amount ofthe reducing agent to be used is about 0.75 to about 10 equivalents,preferably about 1 to about 5 equivalents, per 1 mol of compound (IV).

This reaction is advantageously performed using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, solvents such as hydrocarbons (e.g., benzene, tolueneand the like), ethers (e.g., tetrahydrofuran, diethyl ether and thelike) and the like, a mixed solvent thereof and the like are preferable.

While the reaction time varies depending on the reagents and solvent tobe used, it is generally about 30 min to about 24 hr, preferably about30 min to about 8 hr.

The reaction temperature is generally about −78° C. to about 100° C.,preferably about −78° C. to about 25° C.

Compound (VI) wherein each symbol in the formula is as defined above canbe synthesized by reacting compound (V) with an oxidant such as chromicacid-pyridine complex, pyridinium chlorochromate, manganese dioxide,sulfur trioxide-pyridine complex, tetra-n-propylammonium perruthenateand the like. As the oxidant, manganese dioxide, sulfurtrioxide-pyridine complex or tetra-n-propylammonium perruthenate ispreferable. The oxidation reaction can be performed, for example,according to the method described in Synthesis, p. 639 (1994).

Compound (I) wherein each symbol is as defined above can be produced bysubjecting compound (VI) and a compound represented by the formula (VII)

wherein R⁴ and R⁵ are as defined above, to a reductive aminationreaction according to, for example, the method described in JikkenKagaku Koza (Courses in Experimental Chemistry), vol. 14-111, page1380-1385 (1978), (Maruzen Press).

In each of the above-mentioned reaction steps for deriving compound (I)from compound (II), when desired, protection or deprotection, acylationreaction, alkylation reaction, hydrogenation reaction, oxidationreaction, reduction reaction, carbon chain extension reaction,substituent exchange reaction and the like may be applied individuallyor in a combination of two or more thereof to various intermediates, or,after deriving a compound encompassed in compound (I), theaforementioned reactions may be combined to further lead the compound toa desired embodiment.

The synthesis method of compound (Ia) is now explained.

compounds (VIII) and (X) wherein R², R⁶ and R⁷ are as defined above, andR⁹ is a C₁₋₄ alkyl group such as methyl, ethyl, propyl, isopropyl orbutyl and the like may be commercially available products, or can beproduced by a method known per se, for example, the methods described inJ.C.S. Chem. Commun., page 26 (1983), J. Heterocyclic. Chem., vol. 13,page 1145 (1976), WO04/7478 and J. Med. Chem., vol. 35, page 4195 (1992)and the like, or a method analogous thereto.

Compound (IX) wherein each symbol is as defined above can be produced byreacting compound (VIII) with a compound represented by the formula(III)

wherein each symbol is as defined above, and X¹ is a hydrogen atom or aleaving group such as halogen (e.g., fluorine, chlorine, bromine,iodine) and the like.

This reaction is advantageously performed using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, hydrocarbons such as benzene, toluene and the like,ethers such as tetrahydrofuran and the like, amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like, and the likeor a mixed solvent thereof and the like are preferable.

Use of a base is effective for the reaction. As the base, for example,inorganic bases such as sodium hydride, sodium hydroxide, potassiumhydroxide and the like, basic salts such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydrogen carbonate and the like,metal bases such as potassium ethoxide, potassium tert-butoxide, sodiummethoxide, sodium ethoxide and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like, and the like canbe mentioned. The amount of the base to be used is about 1 to about 10mol, preferably about 1 to about 5 mol, per 1 mol of compound (VIII).

In addition, this reaction can also be performed in the co-presence ofcrown ether or a halogenating agent. Examples of the crown ether include15-crown-5-ether, 18-crown-6-ether and the like, and examples of thehalogenating agent include N-iodosuccinimide, N-bromosuccinimide,N-chlorosuccinimide, bromine and the like. The amount of these crownether and halogenating agent to be used is, about 1-about 10 mol,preferably about 1-about 5 mol, per 1 mol of compound (VIII),respectively.

While the reaction time varies depending on the reagents and solvent tobe used, it is generally about 30 min to about 24 hr, preferably about30 min to about 8 hr.

The reaction temperature is generally about 0° C. to about 100° C.,preferably about 10° C. to about 50° C.

Compound (IX) can be produced by reacting compound (X) with a compoundrepresented by the formula (XI)

R¹—X²  (XI)

wherein each symbol is as defined above, and X² is a leaving group suchas halogen (e.g., fluorine, chlorine, bromine, iodine),methanesulfonyloxy and the like.

This reaction is advantageously performed using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, hydrocarbons such as benzene, toluene and the like,ethers such as tetrahydrofuran and the like, amides such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpiperidone and thelike, and the like or a mixed solvent thereof and the like arepreferable.

Use of a base is effective for the reaction. As the base, for example,inorganic bases such as sodium hydride, sodium hydroxide, potassiumhydroxide and the like, basic salts such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydrogen carbonate and the like,metal bases such as potassium ethoxide, potassium tert-butoxide, sodiummethoxide, sodium ethoxide and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like, and the like canbe mentioned. The amount of the base to be used is about 1 to about 10mol, preferably about 1 to about 5 mol, per 1 mol of compound (X).

While the reaction time varies depending on the reagents and solvent tobe used, it is generally about 30 min to about 24 hr, preferably about30 min to about 8 hr.

The reaction temperature is generally about 0° C. to about 200° C.,preferably about 10° C. to about 100° C.

Compound (XII) wherein each symbol is as defined above can be producedby reducing compound (IX) with a reducing agent such as lithium aluminumhydride, diisobutylaluminum hydride, sodium borohydride, calciumbis(borohydride) and the like. As the reducing agent, particularlydiisobutylaluminum hydride is preferable. The amount of these reducingagents to be used is about 0.75-about 10 equivalents, preferably about1-about 5 equivalents, per 1 mol of compound (IX).

This reaction is advantageously performed using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, hydrocarbons such as benzene, toluene and the like,ethers such as tetrahydrofuran, diethyl ether and the like, and the likeor a mixed solvent thereof and the like are preferable.

While the reaction time varies depending on the reagents and solvent tobe used, it is generally about 30 min to about 24 hr, preferably about30 min to about 8 hr.

The reaction temperature is generally about −78° C. to about 100° C.,preferably about −78° C. to about 25° C.

compound (XIII) (wherein each symbol is as defined above) can besynthesized by reacting compound (XII) with an oxidant such as chromicacid•pyridine complex, pyridinium chlorochromate, manganese dioxide,sulfur trioxide•pyridine complex or tetra-n-propylammonium perruthenateand the like. As the oxidant, manganese dioxide, sulfurtrioxide•pyridine complex or tetra-n-propylammonium perruthenate ispreferable. This oxidation reaction can be performed, for example,according to the method described in Synthesis, p. 639 (1994).

Compound (Ia) (wherein each symbol is as defined above) can be producedby subjecting compound (XIII) and a compound represented by the formula(VII)

wherein R⁴, R⁵ are as defined above to a reductive amination reactionaccording to, for example, the method described in Jikken Kagaku Koza(Courses in Experimental Chemistry), vol. 14-III, pp. 1380-1385 (1978)(Maruzen Press).

In each of the above-mentioned reaction steps to derive compound (Ia)from compound (VIII) or (X), or each of the below-mentioned reactionsteps to derive compound (Ia) from compound (XIV) or (XV), when desired,protection or deprotection, acylation reaction, alkylation reaction,hydrogenation reaction, oxidation reaction, reduction reaction, carbonchain extension reaction, substituent exchange reaction and the like maybe applied individually or in a combination of two or more thereof tovarious intermediates, or, after deriving a compound encompassed incompound (Ia), the aforementioned reactions may be combined to furtherlead the compound to a desired embodiment.

Compounds (XIII) and (Ia) can also be produced by the following method.

Compound (XIV) (wherein each symbol is as defined above) may be acommercially available product, or can be produced by a method known perse, for example, the methods described in J. Med. Chem., vol. 43, p.2165 (2000), Tetrahedron, vol. 46, p. 7587 (1990) and Tetrahedron, vol.57, p. 7813 (2001) and the like, or a method analogous thereto.

Compound (XIII) (wherein each symbol is as defined above) can beproduced by treating compound (XIV) by a method for producing compound(IX) from compound (VIII) or a method analogous thereto, or treatingcompound (XV) by formylation according to a method described in, forexample, 4th Ed. Jikken Kagaku Koza (Courses in Experimental Chemistry),vol. 21, pp. 106-124 (1991) (Maruzen Press) and the like or a methodanalogous thereto.

In addition, compound (Ia) can also be produced by the following method.

Compounds (XVI) and (XX) (wherein each symbol is as defined above) canbe produced by a method known per se, for example, the methods describedin J. Org. Chem., vol. 46, p. 2596 (1981) and Org. Lett., vol. 3, p.1261 (2001) and the like, or a method analogous thereto.

Compound (XVII) (wherein each symbol is as defined above, and X³ is aleaving group such as halogen (e.g., fluorine, chlorine, bromine,iodine) and the like) can be obtained by treating compound (XVI) with ahalogen such as chlorine, bromine, iodine and the like or a metal halidesuch as copper (II) bromide, copper (II) chloride and the like.

The amount of halogen or metal halide to be used is about 1 to about 5mol, preferably about 1 to about 2 mol, per 1 mol of compound (XVI).

This reaction is advantageously performed without solvent or in thepresence of a solvent inert to the reaction. While the solvent is notparticularly limited as long as the reaction proceeds, for example,ethers, esters, aromatic hydrocarbons, aliphatic hydrocarbon, amides,halogenated hydrocarbons, nitriles, sulfoxides, organic acids, aromaticamines or a mixture of two or more kinds thereof and the like are used.

This reaction can also be performed in the co-presence of an acid orbase.

As the acid, for example, inorganic acids such as hydrochloric acid,hydrobromic acid and the like, and the like can be mentioned. As thebase, for example, metal hydroxides such as sodium hydroxide, potassiumhydroxide, lithium hydroxide and the like, basic salts such as sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium acetate and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like, and the like canbe mentioned. The amount of the acid to be used is about 0.01 to about 3mol, preferably about 0.01 to about 1 mol, per 1 mol of compound (XVI).The amount of the base to be used is about 1 to about 10 mol, preferablyabout 1 to about 3 mol, per 1 mol of compound (XVI).

While the reaction time varies depending on the reagent and solvent tobe used, it is generally about 5 min-about 24 hr, preferably about 10min-about 5 hr.

The reaction temperature is generally about −20° C.-about 150° C.,preferably about 0° C.-about 100° C.

Compound (XIX) can be obtained by condensing compound (XVII) and acompound represented by the formula (XVIII)

wherein Y is an oxygen atom, a sulfur atom or a nitrogen atom (NH).

When compound (XVIII) is commercially available, a commerciallyavailable product may be directly used, or obtained by a method knownper se or a method analogous thereto and the like.

The amount of compound (XVIII) to be used is about 0.5 to about 3 mol,preferably about 0.8 to about 2 mol, per 1 mol of compound (XVII).

This reaction is advantageously performed without solvent or in thepresence of a solvent inert to the reaction. While the solvent is notparticularly limited as long as the reaction proceeds, for example,halogenated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons,ethers, amides, alcohols, nitriles or a mixture of two or more kindsthereof and the like are used.

When desired, this reaction can also be performed in the co-presence ofa base. As the base, for example, basic salts such as sodium carbonate,potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodiumacetate and the like, aromatic amines such as pyridine, lutidine and thelike, tertiary amines such as triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine and the like, and the like can be mentioned. Theamount of the base to be used is about 1 to about 30 mol, preferablyabout 1 to about 10 mol, per 1 mol of compound (XVII).

While the reaction time varies depending on the reagent and solvent tobe used, it is generally about 5 min-about 72 hr, preferably about0.5-about 30 hr.

The reaction temperature is generally about −5° C.-about 200° C.,preferably about 5° C.-about 150° C.

Compound (XIX) (wherein each symbol is as defined above) can be producedby treating compound (XX) by a method for producing compound (IX) fromcompound (VIII) or a method analogous thereto.

Compound (Ia) (wherein each symbol is as defined above) can be producedby reacting compound (XIX) with a compound represented by the formula(XXI)

R⁴—X⁴  (XXI)

wherein each symbol is as defined above, X⁴ is a leaving group such ashalogen (e.g., fluorine, chlorine, bromine, iodine), methanesulfonyloxyand the like.

This reaction is advantageously performed using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, hydrocarbons such as benzene, toluene and the like,ethers such as tetrahydrofuran and the like, amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like, and the likeor a mixed solvent thereof and the like is preferable.

Use of a base is effective for the reaction. As the base, for example,inorganic bases such as sodium hydride, sodium hydroxide, potassiumhydroxide and the like, basic salts such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydrogen carbonate and the like,metal bases such as potassium ethoxide, potassium tert-butoxide, sodiummethoxide, sodium ethoxide and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like, and the like canbe mentioned. The amount of the base to be used is about 1 to about 10mol, preferably about 1 to about 5 mol, per 1 mol of compound (XIX).

While the reaction time varies depending on the reagents and solvent tobe used, it is generally about 30 min to about 24 hr, preferably about30 min to about 8 hr.

The reaction temperature is generally about −20° C. to about 100° C.,preferably about 0° C. to about 50° C.

In each of the above-mentioned reaction step to derive compound (Ia)from compound (XVI) or (XX), when desired, protection or deprotection,acylation reaction, alkylation reaction, hydrogenation reaction,oxidation reaction, reduction reaction, carbon chain extension reaction,substituent exchange reaction and the like may be applied individuallyor in a combination of two or more thereof to various intermediates, or,after deriving a compound encompassed in compound (Ia), theaforementioned reactions may be combined to further lead the compound toa desired embodiment.

In each of the aforementioned reaction, when a starting materialcompound has an amino group, a carboxyl group or a hydroxyl group as asubstituent, these groups may be protected by a protecting groupgenerally used for peptide chemistry and the like. In this case, theobject compound can be obtained by removing the protecting group asnecessary after the reaction. Such protecting groups can be introducedor removed by a method known per se, for example, the method describedin “Protective Groups in Organic Synthesis, 3rd Ed.” (Theodora W.Greene, Peter G. M. Wuts, Wiley-Interscience (1999)) and the like.

Compound (I) can be isolated and purified by a known means such as phasetransfer, concentration, solvent extraction, fractionation, liquidconversion, crystallization, recrystallization, chromatography and thelike.

When compound (I) is obtained as a free compound, it can be converted toa desired salt by a method known per se or a method analogous thereto;conversely, when compound (I) is obtained as a salt, it can be convertedinto a free form or another desired salt by a method known per se or amethod analogous thereto.

Compound (I) may be used as a prodrug. The prodrug of compound (I) meansa compound which is converted to compound (I) under the physiologicalcondition in the body by a reaction with an enzyme, gastric acid, or thelike, that is, a compound which is converted to compound (I) byenzymatic oxidation, reduction, hydrolysis, and the like; a compoundwhich is converted to compound (I) by hydrolysis and the like withgastric acid, and the like.

The prodrug of compound (I) includes a compound wherein the amino groupof compound (I) is modified with acyl, alkyl or phosphoryl (e.g., acompound wherein the amino group of compound (I) is modified witheicosanoyl, alanyl, pentylaminocarbonyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl,pyrrolidylmethyl, pivaloyloxymethyl or t-butyl, etc.); a compoundwherein the hydroxyl group of compound (I) is modified with acyl, alkyl,phosphoryl or borate (e.g., a compound wherein the hydroxyl group ofcompound (I) is modified with acetyl, palmitoyl, propanoyl, pivaloyl,succinyl, fumaryl, alanyl or dimethylaminomethylcarbonyl, etc.); acompound wherein a carboxyl group of compound (I) is modified to esteror amide (e.g., a compound wherein a carboxyl group of compound (I) ismodified to ethyl ester, phenyl ester, carboxymethyl ester,dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester or methylamide, etc.); and the like.These compounds can be produced from compound (I) by a method known perse.

In addition, the prodrug of compound (I) may be a compound, which isconverted to compound (I) under the physiological conditions, asdescribed in Pharmaceutical Research and Development, Vol. 7 (MoleculeDesign), pp. 163-198 (1990), published by Hirokawa Publishing Co.

When compound (I) contains isomers such as an optical isomer, astereoisomer, a regioisomer, a rotamer and the like, any of theseisomers and a mixture of these are also encompassed in compound (I). Forexample, when compound (I) has an optical isomer, an optical isomerresolved from a racemate is also encompassed in compound (I). Theseisomers can be obtained as single products according to synthesis andseparation methods known per se (concentration, solvent extraction,column chromatography, recrystallization, etc.)

The compound (I) may be a crystal, and both a single crystalline formand crystalline form mixture are encompassed in compound (I). Crystalscan be produced by crystallization according to crystallization methodsknown per se.

The compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate,both of which are encompassed in the compound (I).

A compound labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I, and thelike) is also encompassed in the compound (I).

Compound (I) and a prodrug thereof of the present invention (hereinaftersometimes to be abbreviated as the compound of the present invention)have a proton pump inhibitory action and effectively suppress gastricacid secretion. In addition, since they show low toxicity (e.g., acutetoxicity, chronic toxicity, genetic toxicity, reproductive toxicity,cardiotoxicity, drug interaction, carcinogenicity and the like) and highwater-solubility, and are superior in the stability, in vivo kinetics(absorbability, distribution, metabolism, excretion and the like), andefficacy expression, they are useful as pharmaceutical agents.

The compound of the present invention is useful for the prophylaxis ortreatment of peptic ulcer (e.g., gastric ulcer, gastric ulcer due topostoperative stress, duodenal ulcer, anastomotic ulcer, ulcer caused bynon-steroidal anti-inflammatory agent etc.); gastritis; erosiveesophagitis; nonerosive esophagitis; reflux esophagitis such as erosivereflux esophagitis and the like; symptomatic gastroesophageal refluxdisease (Symptomatic GERD) such as nonerosive esophageal reflux,esophageal reflux unaccompanied by esophagitis and the like; functionaldyspepsia including NUD (Non Ulcer Dyspepsia); gastric cancer (includinggastric cancer associated with promoted production of interleukin-1β dueto gene polymorphism of interleukin-1); stomach MALT lymphoma;Zollinger-Ellison syndrome; hyperacidity; upper gastrointestinalhemorrhage caused by peptic ulcer, acute stress ulcer, hemorrhagicgastritis, invasive stress (e.g., stress caused by major surgeryrequiring post-operative intensive management, or cerebrovasculardisorder, head trauma, multiple organ failure or extensive burnrequiring intensive treatment) and the like; airway disorders; asthma;and the like, pre-anesthetic administration, eradication or assistant toeradication of Helicobacter pylori and the like in mammals (e.g., human,monkey, sheep, bovine, horse, dog, cat, rabbit, rat, mouse etc.).

As used herein, the above-mentioned reflux esophagitis and symptomaticgastroesophageal reflux disease (symptomatic GERD) are sometimescollectively referred to simply as GERD.

The content of a compound of the present invention in the pharmaceuticalcomposition of the present invention is about 0.01 to 100% by weightrelative to the entire composition. Though subject to change dependingon the administration target, administration route, target disease andthe like, its dose is about 0.5 to 1,500 mg/day, preferably about 5 to150 mg/day, based on the active ingredient, when, for example, thecompound is orally administered as an anti-ulcer agent to an adult human(60 kg). The compound of the present invention may be administered oncedaily or in 2 or 3 divided portions per day.

The compound of the present invention shows low toxicity and can besafely administered orally or parenterally (e.g., topical, rectal,intravenous administrations and the like) as it is or as a preparationcontaining a pharmaceutical composition containing a pharmacologicallyacceptable carrier admixed according to a method known per se, such astablets (including sugar-coated tablets and film-coated tablets),powder, granule, capsule (including soft capsule), orally disintegratingtablet, orally disintegrating film, liquid, injection, suppository,sustained-release preparation, plaster and the like. Particularly, thecompound of the present invention is preferably administered as an oralpreparation in the form of tablet, granule, capsule and the like.

The pharmacologically acceptable carrier that may be used to produce thepharmaceutical composition of the present invention includes variousorganic or inorganic carrier substances in common use as pharmaceuticalmaterials, including excipients, lubricants, binders, disintegrants,water-soluble polymers and basic inorganic salts for solid preparations;and solvents, solubilizing agents, suspending agents, isotonizingagents, buffers and soothing agents for liquid preparations and thelike. Other ordinary additives such as preservatives, anti-oxidants,colorants, sweetening agents, souring agents, bubbling agents andflavorings may also be used as necessary.

Such “excipients” include, for example, lactose, sucrose, D-mannitol,starch, cornstarch, crystalline cellulose, light anhydrous silicic acid,titanium oxide and the like.

Such “lubricants” include, for example, magnesium stearate, sucrosefatty acid esters, polyethylene glycol, talc, stearic acid and the like.

Such “binders” include, for example, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, crystalline cellulose, starch,polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan,low-substituted hydroxypropyl cellulose and the like.

Such “disintegrants” include (1) crosspovidone, (2) what is calledsuper-disintegrants such as crosscarmellose sodium (FMC-Asahi Chemical)and carmellose calcium (Gotoku Yakuhin) etc, (3) sodium carboxymethylstarch (e.g., product of Matsutani Chemical), (4) low-substitutedhydroxypropyl cellulose (e.g., product of Shin-Etsu Chemical), (5) cornstarch, and so forth. Said “crosspovidone” may be any crosslinkedpolymer having the chemical name 1-ethenyl-2-pyrrolidinone homopolymer,including polyvinylpyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinonehomopolymer, and is exemplified by Colidon CL (produced by BASF),Polyplasdon XL (produced by ISP), Polyplasdon XL-10 (produced by ISP),Polyplasdon INF-10 (produced by ISP) and the like.

Such “water-soluble polymers” include, for example, ethanol-solublewater-soluble polymers [e.g., cellulose derivatives such ashydroxypropyl cellulose (hereinafter also referred to as HPC) etc,polyvinylpyrrolidone and the like], ethanol-insoluble water-solublepolymers [e.g., cellulose derivatives such as hydroxypropylmethylcellulose (hereinafter also referred to as HPMC) etc., methyl cellulose,carboxymethyl cellulose sodium and the like, sodium polyacrylate,polyvinyl alcohol, sodium alginate, guar gum and the like] and the like.

Such “basic inorganic salts” include, for example, basic inorganic saltsof sodium, potassium, magnesium and/or calcium. Preferred are basicinorganic salts of magnesium and/or calcium. More preferred are basicinorganic salts of magnesium. Such basic inorganic salts of sodiuminclude, for example, sodium carbonate, sodium hydrogen carbonate,disodium hydrogenphosphate and the like. Such basic inorganic salts ofpotassium include, for example, potassium carbonate, potassiumhydrogencarbonate and the like. Such basic inorganic salts of magnesiuminclude, for example, heavy magnesium carbonate, magnesium carbonate,magnesium oxide, magnesium hydroxide, magnesium aluminometasilicate,magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg₆Al₂(OH)₁₆. CO₃.4H₂O], and magnesia alumina hydrate. Preferred are heavymagnesium carbonate, magnesium carbonate, magnesium oxide, magnesiumhydroxide and the like. Such basic inorganic salts of calcium include,for example, precipitated calcium carbonate, calcium hydroxide, etc.

Such “solvents” include, for example, water for injection, alcohol,propylene glycol, macrogol, sesame oil, corn oil, olive oil and thelike.

Such “solubilizing agents” include, for example, polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Such “suspending agents” include, for example, surfactants such asstearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, benzalkonium chloride, benzethonium chloride, glycerylmonostearate etc; hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose,hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl celluloseetc., and the like.

Such “isotonizing agents” include, for example, glucose, D-sorbitol,sodium chloride, glycerol, D-mannitol and the like.

Such “buffers” include, for example, buffer solutions of phosphates,acetates, carbonates, citrates etc, and the like.

Such “soothing agents” include, for example, benzyl alcohol and thelike.

Such “preservatives” include, for example, p-oxybenzoic acid esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Such “antioxidants” include, for example, sulfites, ascorbic acid,α-tocopherol and the like.

Such “colorants” include, for example, food colors such as Food ColorYellow No. 5, Food Color Red No. 2, Food Color Blue No. 2 etc.; foodlake colors, red ferric oxide and the like.

Such “sweetening agents” include, for example, saccharin sodium,dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like.

Such “souring agents” include, for example, citric acid (citricanhydride), tartaric acid, malic acid and the like.

Such “bubbling agents” include, for example, sodium bicarbonate and thelike.

Such “flavorings” may be synthetic substances or naturally occurringsubstances, and include, for example, lemon, lime, orange, menthol,strawberry and the like.

The compound of the present invention may be prepared as a preparationfor oral administration in accordance with a commonly-known method, by,for example, compression-shaping with a carrier such as an excipient, adisintegrant, a binder, a lubricant, or the like, and subsequentlycoating the preparation as necessary by a commonly known method for thepurpose of taste masking, enteric dissolution or sustained release. Foran enteric preparation, an intermediate layer may be provided by acommonly known method between the enteric layer and the drug-containinglayer for the purpose of separation of the two layers.

For preparing the compound of the present invention as an orallydisintegrating tablet, available methods include, for example, a methodin which a core containing crystalline cellulose and lactose is coatedwith the compound of the present invention and, where necessary, a basicinorganic salt, and then further coated with a coating layer containinga water-soluble polymer to give a composition, which is coated with anenteric coating layer containing polyethylene glycol, further coatedwith an enteric coating layer containing triethyl citrate, still furthercoated with an enteric coating layer containing polyethylene glycol, andfinally coated with mannitol to give fine granules, which are mixed withadditives and shaped.

The above-mentioned “enteric coating layer” includes, for example, alayer consisting of a mixture of one or more kinds from aqueous entericpolymer substrates such as cellulose acetate phthalate (CAP),hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetatesuccinate, methacrylic acid copolymers (e.g., Eudragit L30D-55 (tradename; produced by Rohm), Colicoat MAE30DP (trade name; produced byBASF), Polyquid PA30 (trade name; produced by San-yo Chemical) etc.),carboxymethylethyl cellulose, shellac and the like; sustained-releasesubstrates such as methacrylic acid copolymers (e.g., Eudragit NE30D(trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name),etc.) and the like; water-soluble polymers; plasticizers such astriethyl citrate, polyethylene glycol, acetylated monoglycerides,triacetin, castor oil and the like; and the like, and the like.

The above-mentioned “additive” includes, for example, water-solublesugar alcohols (e.g., sorbitol, mannitol, maltitol, reduced starchsaccharides, xylitol, reduced palatinose, erythritol, etc.), crystallinecellulose (e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH301, Avicel PH 302, Avicel RC-591 (crystalline cellulose•carmellosesodium) etc.), low-substituted hydroxypropyl cellulose (e.g., LH-22,LH-32, LH-23, LH-33 (Shin-Etsu Chemical), mixtures thereof etc.) and thelike. Furthermore, binders, souring agents, bubbling agents, sweeteningagents, flavorings, lubricants, colorants, stabilizers, excipients,disintegrants etc. are also used.

The compound of the present invention may be used in combination with 1to 3 other active ingredients.

Such “other active ingredients” include, for example, anti-Helicobacterpylori active substances, imidazole compounds, bismuth salts, quinolonecompounds, and so forth.

Examples of the “anti-Helicobacter pylori active substance” includepenicillin antibiotic (e.g., amoxicillin, benzylpenicillin,piperacillin, mecillinam etc.), cephem antibiotic (e.g., cefixime,cefaclor etc.), macrolide antibiotic (e.g., erythromycin, clarithromycinetc.), tetracycline antibiotic (e.g., tetracycline, minocycline,streptomycin etc.), aminoglycoside antibiotic (e.g., gentamicin,amikacin etc.), imipenem and the like. Of these, penicillin antibiotic,macrolide antibiotic and the like are preferable.

Such “imidazole compounds” include, for example, metronidazole,miconazole and the like.

Such “bismuth salts” include, for example, bismuth acetate, bismuthcitrate and the like.

Such “quinolone compounds” include, for example, ofloxacin, ciploxacinand the like.

Particularly, for eradication of Helicobacter pylori, a compound (I) ora salt thereof of the present invention with antibiotic penicillin(e.g., amoxicillin and the like) and antibiotic erythromycin (e.g.,clarithromycin and the like) is preferably used.

For the purpose of eradication of Helicobacter pylori, the compound ofthe present invention can enhance antibacterial action of otherantibiotics based on the pH controlling action in the stomach and thelike, and also provides an assistant effect such as an eradicationeffect based on the action of the antibiotics to be used in combination.

Such “other active ingredients” and the compound (I) or a salt thereofof the present invention may be mixed, prepared as a singlepharmaceutical composition [e.g., tablets, powders, granules, capsules(including soft capsules), liquids, injectable preparations,suppositories, sustained-release preparations, etc.], in accordance witha commonly known method, and used in combination, and may also beprepared as separate preparations and administered to the same subjectsimultaneously or at a time interval.

In addition, the compound of the present invention may be used incombination with a gastric motility enhancer, a drug acting on loweresophageal sphincter (e.g., temporary lower esophageal sphincterrelaxation suppressant etc.), ClC-2 channel opener (intestinal juicesecretion enhancer), a histamine H₂ receptor antagonist, an antacid, asedative, a stomachic digestant or a non-steroidal anti-inflammatorydrug (NSAID).

As the “gastric motility enhancer”, for example, domperidone,metoclopramide, mosapride, itopride, tegaserod and the like can bementioned.

As the “a drug acting on lower esophageal sphincter”, for example,GABA-B receptor agonists such as baclofen, an optically active formthereof etc., and the like can be mentioned.

As the “ClC-2 channel opener (intestinal juice secretion enhancer)”,lubiprostone and the like can be mentioned.

As the “histamine H₂ receptor antagonist”, cimetidine, ranitidine,famotidine, roxatidine, nizatidine, lafutidine and the like can bementioned.

As the “antacid”, sodium hydrogen carbonate, aluminum hydroxide and thelike can be mentioned.

As the “sedatives”, diazepam, chlordiazepoxide and the like can bementioned.

As the “stomachic digestant”, gentiana, swertia japonica, diastase andthe like can be mentioned.

As the “non-steroidal anti-inflammatory drug”, for example, aspirin,indomethacin, ibuprofen, mefenamic acid, diclofenac, etodorac,piroxicam, celecoxib and the like can be mentioned.

A gastric motility enhancer, a drug acting on lower esophagealsphincter, a ClC-2 channel opener (intestinal juice secretion enhancer),a histamine H₂ receptor antagonist, an antacid, a sedative, a stomachicdigestant or a non-steroidal anti-inflammatory drug and compound (I) ora salt thereof of the present invention may be mixed, prepared as asingle pharmaceutical composition [e.g., tablets, powders, granules,capsules (including soft capsules), liquids, injections, suppositories,sustained-release preparations, etc.] according to a method known per sefor combined use, or may also be prepared as separate preparations andadministered to the same subject simultaneously or in a staggeredmanner.

The compound of the present invention may be used in combination withthe following drugs.

(i) proton pump inhibitor, for example, omeprazole, esomeprazole,pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lansoprazole;

(ii) oral antacid combination agent, for example, Maalox, Aludrox andGaviscon;

(iii) mucous membrane protector, for example, polaprezinc, ecabe sodium,rebamipide, teprenone, cetraxate, sucralfate, chloropylline-copper andplaunotol;

(iv) antigastric agent, for example, anti-gastrin vaccine, itriglumideand Z-360;

(v) 5-HT₃ antagonist, for example, dolasetron, palonosetron, alosetron,azasetron, ramosetron, mitrazapine, granisetron, tropisetron, E-3620,ondansetron and indisetron;

(vi) 5-HT₄ agonist, for example, tegaserod, mosapride, cinitapride andoxtriptane;

(vii) laxative agent, for example, Trifyba, Fybogel, Konsyl, Isogel,Regulan, Celevac and Normacol;

(viii) GABA_(B) agonist, for example, baclofen and AZD-3355;

(ix) GABA_(B) antagonist, for example, GAS-360 and SGS-742;

(x) calcium channel blocker, for example, aranidipine, lacidipine,falodipine, azelnidipine, clinidipine, lomerizine, diltiazem,gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine,bevantolol, nicardipine, isradipine, benidipine, verapamil,nitrendipine, barnidipine, propafenone, manidipine, bepridil,nifedipine, nilvadipine, nimodipine and fasudil;

(xi) dopamine antagonist, for example, metoclopramide, domperidone andlevosulpiride;

(xii) tachykinin (NK) antagonist, particularly, NK-3, NK-2 and NK-1antagonist, for example, nepadutant, saredutant, talnetant,((R,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6-13-dione(TAK-637),5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), lanepitant, dapitant and3-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine(2S,3S);

(xiii) nitric monoxide synthase inhibitor, for example, GW-274150,tilarginine, P54, guanidioethyldisulfide and nitroflurbiprofen;

(xiv) vanilloid receptor 1 antagonist, for example, AMG-517 andGW-705498;

(xv) ghrelin agonist, for example, capromorelin and TZP-101;

(xvi) AchE release stimulant, for example, Z-338 and KW-5092.

The above-mentioned drugs (i)-(xvi) and compound (I) or a salt thereofof the present invention may be mixed, prepared as a singlepharmaceutical composition [e.g., tablets, powders, granules, capsules(including soft capsules), liquids, injections, suppositories,sustained-release preparations, etc.] according to a method known per sefor combined use, or may also be prepared as separate preparations andadministered to the same subject simultaneously or in a staggeredmanner.

EXAMPLES

The present invention is explained in detail in the following byreferring to Reference Examples, Examples and Experimental Examples,which are not to be construed as limitative.

In the following Reference Examples and Examples, the “room temperature”generally means about 10° C. to about 35° C., but it is not particularlystrictly limited. The mixing ratio of liquids shows a volume ratio.Unless otherwise specified, “%” means weight %. The yield is in mol/mol%. Silica gel column chromatography was performed using silica gel 60(0.063-0.200 mm) manufactured by MERCK, Fuji Silysia Chemical Ltd.Chromatorex (trade name) NH (described as basic silica gel columnchromatography). For ¹H-NMR spectrum, tetramethylsilane was used as theinternal standard, and Varian Gemini-200 (200 MHz), Mercury-300 (300MHz) spectrometer, Bruker AVANCE AV300 (300 MHz) and JNM-AL400 (400 MHz)nuclear magnetic resonance apparatuses JEOL DATUM (JEOL DATUM LTD.) wereused for the measurement. The following abbreviations are used forshowing the measurement results.

s: singlet, d: doublet, dd: double doublet, dt: double triplet, t:triplet, q: quartet, m: multiplet, br: broad, brs: broad singlet, J:coupling constant, Hz: Hertz.

Reference Example 1 Methyl 4-methyl-1H-pyrrole-3-carboxylate

To a suspension of potassium tert-butoxide (76.7 g) in tetrahydrofuran(900 mL) was added dropwise a solution of p-toluenesulfonylmethylisocyanide (94.6 g) and methyl crotonate (48.5 g) in tetrahydrofuran(900 mL) over 30 min. The reaction mixture was stirred at roomtemperature for 3 hr, water was added, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent:hexane-ethyl acetate=4:1) to give the title compound as a whitesolid (yield 16.8 g, 25%).

¹H-NMR (CDCl₃) δ: 2.29 (3H, s), 3.80 (3H, s), 6.53-6.54 (1H, m),7.36-7.38 (1H, m), 8.25 (1H, brs).

Reference Example 2 Methyl 4-methyl-1-phenyl-1H-pyrrole-3-carboxylate

To a solution of methyl 4-methyl-1H-pyrrole-3-carboxylate (1.70 g) inN,N-dimethylformamide (1.5 mL) were added iodobenzene (1.50 mL),potassium carbonate (2.19 g), L-proline (273 mmg) and copper iodide (232mg), and the reaction was carried out in a microwave reactor (EmrysOptimizer manufactured by Personal Chemistry, 70° C., 1 hr). Thereaction mixture was filtered through celite, water was added to thefiltrate, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent:hexane-ethyl acetate=9:1-2:1)to give the title compound as a colorless solid (yield 925 mg, 35%).

¹H-NMR (CDCl₃) δ: 2.33 (3H, s), 3.82 (3H, s), 6.80-6.85 (1H, m),7.20-7.50 (5H, m), 7.60-7.65 (1H, m).

Reference Example 3 Methyl4-methyl-1-phenyl-5-(phenylthio)-1H-pyrrole-3-carboxylate

To a solution of methyl 4-methyl-1-phenyl-1H-pyrrole-3-carboxylate (540mg) in tetrahydrofuran (10 mL) were added N-iodosuccinimide (677 mg) andthiophenol (0.257 mL), and the mixture was stirred at room temperaturefor 2 days. Saturated aqueous sodium thiosulfate solution (10 mL) wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure togive the title compound as a pale-yellow oil (yield 812 mg, about 100%).

¹H-NMR (CDCl₃) δ: 2.45 (3H, s), 3.85 (3H, s), 6.87 (2H, dd, J=7.8, 1.6Hz), 7.05-7.40 (8H, m), 7.66 (1H, s).

Reference Example 4 Methyl4-methyl-1-phenyl-5-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

To a solution of methyl4-methyl-1-phenyl-5-(phenylthio)-1H-pyrrole-3-carboxylate (812 mg) inethyl acetate (15 mL) was added 3-chloroperbenzoic acid (1.08 g), andthe mixture was stirred at room temperature for 18 hr. Furthermore,3-chloroperbenzoic acid (1.08 g) was added, and the mixture was stirredat room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the titlecompound as a pale-yellow solid (yield 414 mg, 46%).

¹H-NMR (CDCl₃) δ: 2.82 (3H, s), 3.81 (3H, s), 7.00-7.10 (2H, m),7.20-7.60 (9H, m).

Reference Example 54-methyl-1-phenyl-5-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

A solution of methyl4-methyl-1-phenyl-5-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (410 mg)in tetrahydrofuran (10 mL) was cooled to −78° C., and 1.5 mol/L toluenesolution of diisobutylaluminum hydride (2.3 mL) was added dropwise.After the completion of the dropwise addition, the mixture was stirredat room temperature for 30 min. Saturated brine was added, and themixture was stirred at room temperature for 30 min. The reaction mixturewas filtered through celite, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Asolution of the residue in acetonitrile (10 mL) was cooled to 0° C.,tetra-n-propylammonium perruthenate (40 mg), N-methylmorpholine N-oxide(269 mg) and molecular sieves 4A powder (1.0 g) were added, and themixture was stirred at room temperature for 2.5 hr. The reaction mixturewas concentrated under reduced pressure, and the residue was suspendedin ethyl acetate and filtered through celite. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1)to give the title compound as a pale-yellow oil (yield 170 mg, 45%).

¹H-NMR (CDCl₃) δ: 2.85 (3H, s), 7.04 (2H, d, J=8.0 Hz), 7.20-7.60 (9H,m), 9.94 (1H, s).

Reference Example 6 2-nitro-1-phenylpropan-1-ol

To a solution of benzaldehyde (20.0 g) and nitroethane (28.4 g) intetrahydrofuran (50 mL) and tert-butanol (50 mL) was added potassiumtert-butoxide (1.27 g) under ice-cooling, and the mixture was stirred atroom temperature for 16 hr. Water was added to the reaction mixture, andthe mixture was extracted with diethyl ether. The extract was washedwith saturated aqueous sodium hydrogen carbonate solution and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent:hexane-ethyl acetate=10:1) to give the titlecompound as a blue oil (yield 32.0 g, 93%).

¹H-NMR (CDCl₃) δ: 1.23-1.34 (3H, m), 2.56-2.70 (1H, m), 4.68-4.80 (1H,m), 5.01-5.42 (1H, m), 7.32-7.41 (5H, m).

Reference Example 7 2-nitro-1-phenylpropyl acetate

To a solution of 2-nitro-1-phenylpropan-1-ol (32 g) and acetic anhydride(22 mL) in diethyl ether (300 mL) was added 4-dimethylaminopyridine(0.61 g) under ice-cooling, and the mixture was stirred at roomtemperature for 1 hr. Methanol was added to the reaction mixture, andthe mixture was further stirred for 30 min and concentrated underreduced pressure. Water was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogen carbonate solution, water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give the title compound as a yellow oil (yield 34 g, 86%).

¹H-NMR (CDCl₃) δ: 1.33-1.58 (3H, m), 2.01-2.15 (3H, m), 4.77-4.99 (1H,m), 6.03-6.35 (1H, m), 7.30-7.43 (5H, m).

Reference Example 84-methyl-2-[(4-methylphenyl)sulfonyl]-3-phenyl-1H-pyrrole

To a solution of p-toluenesulfonylmethyl isocyanide (6.1 g) and1,1,3,3-tetramethylguanidine (8.3 mL) in tetrahydrofuran (18 mL) andisopropyl alcohol (18 mL) was added dropwise a solution of2-nitro-1-phenylpropyl acetate (7.0 g) in tetrahydrofuran (3 mL) andisopropyl alcohol (3 mL), and the mixture was stirred at roomtemperature for 4 hr. Water was added to the reaction mixture, and themixture was extracted with a mixed solvent of ethyl acetate andtetrahydrofuran. The extract was washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was recrystallized from ethyl acetate-hexane togive the title compound as a white solid (yield 6.1 g, 63%).

¹H-NMR (CDCl₃) δ: 1.92 (3H, s), 2.32 (3H, s), 6.78-6.80 (1H, m),7.03-7.07 (2H, m), 7.17-7.22 (2H, m), 7.26-7.37 (5H, m), 9.09 (1H, brs).

Reference Example 93-methyl-5-[(4-methylphenyl)sulfonyl]-4-phenyl-1H-pyrrole-2-carbaldehyde

4-Methyl-2-[(4-methylphenyl)sulfonyl]-3-phenyl-1H-pyrrole (374 mg) and(chloromethylene)dimethylammonium chloride (872 mg) were stirred at 60°C. for 16 hr in a mixed solvent of tetrahydrofuran (10 mL) andacetonitrile (5 mL). The reaction mixture was cooled to roomtemperature, saturated aqueous sodium hydrogen carbonate solution wasadded, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated aqueous sodium hydrogen carbonate solution, waterand saturated brine in this order, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent:hexane-ethylacetate=4:1) to give the title compound as a pale-yellow solid (yield187 mg, 46%).

¹H-NMR (CDCl₃) δ: 2.18 (3H, s), 2.34 (3H, s), 7.07-7.16 (4H, m),7.26-7.29 (2H, m), 7.34-7.41 (3H, m), 9.79 (1H, brs), 9.84 (1H, s).

Reference Example 101-[(4-methylphenyl)sulfonyl]-2-phenyl-1H-imidazole-4-carbaldehyde

To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) inN,N-dimethylformamide (35 mL) was added sodium hydride (60% in oil, 483mg) at room temperature, and the mixture was stirred for 1 hr.4-Methylphenylsulfonyl chloride (1.92 g) was added, and the mixture wasstirred at 50° C. for 30 min. The reaction mixture was cooled, water wasadded, and the mixture was extracted with ethyl acetate. The extract waswashed with water, 1 mol/L hydrochloric acid and saturated aqueoussodium hydrogen carbonate solution, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent:hexane-ethylacetate=9:1-7:3), and crystallized from diisopropyl ether to give thetitle compound as colorless crystals (yield 1.95 g, 60%).

¹H-NMR (CDCl₃) δ: 2.39 (3H, s), 7.15 (2H, d, J=8.2 Hz), 7.28 (2H, d,J=8.2 Hz), 7.37-7.42 (4H, m), 7.49-7.54 (1H, m), 8.29 (1H, s), 9.93 (1H,s).

Reference Example 111-(mesitylsulfonyl)-2-phenyl-1H-imidazole-4-carbaldehyde

To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) inN,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 523mg) at room temperature, and the mixture was stirred for 1 hr.Mesitylsulfonyl chloride (2.42 g) was added, and the mixture was stirredfor 1 hr. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogen carbonate solution, 3% aqueous potassiumhydrogensulfate solution and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent:hexane-ethylacetate=7:3-3:2) to give the title compound as a pale-yellow oil (yield1.76 g, 49%).

¹H-NMR (CDCl₃) δ: 2.17 (6H, s), 2.26 (3H, s), 6.78 (2H, s), 7.15-7.23(4H, m), 7.34-7.38 (1H, m), 8.33 (1H, s), 9.96 (1H, s)

Reference Example 122-phenyl-1-(pyridin-3-ylsulfonyl)-1H-imidazole-4-carbaldehyde

To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.00 g) intetrahydrofuran (50 mL) was added sodium hydride (60% in oil, 697 mg) atroom temperature, and the mixture was stirred for 30 min. 15-Crown-5(3.84 g) was added dropwise, and the mixture was further stirred for 10min. 3-Pyridylsulfonyl chloride hydrochloride (1.62 g) was added to thereaction mixture, and the mixture was stirred for 2 hr. Saturatedaqueous sodium hydrogen carbonate solution was added, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent:hexane-ethyl acetate=3:2→2:3), and the obtainedoil was crystallized from diisopropyl ether to give the title compoundas colorless crystals (yield 754 mg, 41%).

¹H-NMR (CDCl₃) δ: 7.29-7.33 (1H, m), 7.37-7.45 (4H, m), 7.53-7.64 (2H,m), 8.33 (1H, s), 8.56 (1H, d, J=2.4 Hz), 8.79 (1H, dd, J=4.9, 1.5 Hz),9.95 (1H, s).

Reference Example 131-[(3-methoxyphenyl)sulfonyl]-2-phenyl-1H-imidazole-4-carbaldehyde

To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (520 mg) intetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 182 mg)at room temperature, and the mixture was stirred for 30 min.3-Methoxybenzenesulfonyl chloride (750 mg) was added to the reactionmixture, and the mixture was stirred for 1.5 hr. Water was added, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was crystallized fromdiethyl ether to give the title compound as colorless crystals (yield894 mg, 87%).

¹H-NMR (CDCl₃) δ: 3.66 (3H, s), 6.81-6.82 (1H, m), 7.01-7.05 (1H, m),7.08-7.12 (1H, m), 7.25-7.31 (1H, m), 7.37-7.44 (4H, m), 7.49-7.54 (1H,m), 8.30 (1H, s), 9.94 (1H, s).

Reference Example 141-[(2,6-difluorophenyl)sulfonyl]-2-phenyl-1H-imidazole-4-carbaldehyde

To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.00 g) intetrahydrofuran (70 mL) was added sodium hydride (60% in oil, 348 mg) atroom temperature, and the mixture was stirred for 30 min.2,6-Difluorobenzenesulfonyl chloride (1.36 g) was added to the reactionmixture, and the mixture was stirred for 1.5 hr. Water was added, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was crystallized fromdiethyl ether to give the title compound as colorless crystals (yield1.36 g, 67%).

¹H-NMR (CDCl₃) δ: 6.82-6.91 (2H, m), 7.27-7.46 (5H, m), 7.51-7.60 (1H,m), 8.38 (1H, s), 9.98 (1H, s).

Reference Example 151-(1-benzothien-2-ylsulfonyl)-2-phenyl-1H-imidazole-4-carbaldehyde

To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (700 mg) intetrahydrofuran (70 mL) was added sodium hydride (60% in oil, 244 mg),and the mixture was stirred for 30 min. 1-Benzothiophene-2-sulfonylchloride (1.04 g) was added to the reaction mixture, and the mixture wasstirred for 1.5 hr. Water was added, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(eluent:hexane-ethyl acetate=7:3) to give the title compound as acolorless oil (yield 1.25 g, 83%).

¹H-NMR (CDCl₃) δ: 7.33-8.08 (10H, m), 8.31 (1H, s), 9.94 (1H, s).

Reference Example 16 Ethyl1-(4-nitrophenyl)-2-[(4-nitrophenyl)thio]-1H-imidazole-4-carboxylate

Ethyl 2-mercapto-1H-imidazole-4-carboxylate (1.00 g),1-fluoro-4-nitrobenzene (2.05 g) and anhydrous potassium carbonate (4.00g) were mixed in N,N-dimethylformamide (30 mL), and the mixture wasstirred at 100° C. for 4 hr. The reaction mixture was cooled, water wasadded, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. Diisopropyl ether was added to theresidue and the resulting crystals were collected by filtration to givethe title compound as pale-yellow crystals (yield 2.06 g, 86%).

¹H-NMR (CDCl₃) δ: 1.43 (3H, t, J=7.2 Hz), 4.46 (2H, q, J=7.2 Hz),7.21-7.26 (2H, m), 7.46-7.51 (2H, m), 8.01 (1H, s) 8.07-8.11 (2H, m),8.31-8.36 (2H, m).

Reference Example 17 Ethyl1-(4-aminophenyl)-2-[(4-aminophenyl)thio]-1H-imidazole-4-carboxylate

Ethyl1-(4-nitrophenyl)-2-[(4-nitrophenyl)thio]-1H-imidazole-4-carboxylate(3.00 g) was suspended in ethanol (120 mL), iron powder (4.05 g),anhydrous calcium chloride (0.81 g) and water (20 mL) were added, andthe mixture was heated under reflux for 4 hr. The reaction mixture wasallowed to cool, and filtered. Saturated aqueous sodium hydrogencarbonate solution was added to the obtained filtrate, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. Methanol (30 mL) was added to the residue and theresulting crystals were collected by filtration to give the titlecompound as pale-yellow crystals (yield 2.00 g, 78%).

¹H-NMR (DMSO-d₆) δ: 1.25 (3H, t, J=7.1 Hz), 4.21 (2H, q, J=7.1 Hz), 5.40(2H, s), 5.49 (2H, s), 6.46-6.51 (2H, m), 6.59-6.64 (2H, m), 6.93-6.97(2H, m), 6.99-7.04 (2H, m), 7.95 (1H, s).

Reference Example 18 Ethyl1-phenyl-2-(phenylthio)-1H-imidazole-4-carboxylate

Ethyl1-(4-aminophenyl)-2-[(4-aminophenyl)thio]-1H-imidazole-4-carboxylate(1.90 g) was dissolved in concentrated hydrochloric acid (30 mL), and asolution of sodium nitrite (1.00 g) in water (5 mL) was added dropwiseat 5-10° C. The mixture was stirred at the same temperature for 1 hr,and the obtained reaction mixture was added dropwise to 50% aqueoushypophosphorous acid solution (30 mL) by small portions. The mixture wasstirred at room temperature for 3 hr, and extracted with ethyl acetate.The extract was washed with saturated aqueous sodium hydrogen carbonatesolution, water and saturated brine in this order, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to give thetitle compound as a yellow oil (yield 1.17 g, 67%).

¹H-NMR (CDCl₃) δ: 1.40 (3H, t, J=7.1 Hz), 4.41 (2H, q, J=7.1 Hz),7.08-7.17 (7H, m), 7.35-7.43 (3H, m), 7.85 (1H, s).

Reference Example 19 [1-phenyl-2-(phenylthio)-1H-imidazol-4-yl]methanol

A solution (30 mL) of ethyl1-phenyl-2-(phenylthio)-1H-imidazole-4-carboxylate (1.17 g) intetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (12 mL)of diisobutylaluminum hydride in toluene was added dropwise by smallportions. The reaction mixture was stirred at 0° C. for 4 hr, water wasadded, and the mixture was stirred for 30 min. To the obtained gel-likesubstance was added tetrahydrofuran, the mixture was filtered, and thefiltrate was concentrated under reduced pressure. A mixed solvent ofethyl acetate-diisopropyl ether (1:1) was added to the residue and theresulting unsoluble crystals were collected by filtration to give thetitle compound as pale-yellow crystals (yield 797 mg, 78%).

¹H-NMR (CDCl₃) δ: 2.59 (1H, br), 4.69 (2H, s), 7.08-7.24 (8H, m),7.37-7.41 (3H, m).

Reference Example 20 1-phenyl-2-(phenylthio)-1H-imidazole-4-carbaldehyde

To a solution of [1-phenyl-2-(phenylthio)-1H-imidazol-4-yl]methanol (740mg) in acetonitrile (50 mL) were added tetra-n-propylammoniumperruthenate (185 mg), N-methylmorpholine N-oxide (1.42 g) and molecularsieves 4A powder (5 g), and the mixture was stirred at room temperaturefor 2 hr. The reaction mixture was filtered through celite, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent:hexane-ethylacetate=3:2) to give the title compound as a pale-yellow oil (yield 400mg, 54%).

¹H-NMR (CDCl₃) δ: 7.18-7.25 (7H, m), 7.41-7.49 (3H, m), 7.85 (1H, s),9.96 (1H, s).

Reference Example 21N-methyl-1-[1-phenyl-2-(phenylthio)-1H-imidazol-4-yl]methanaminedihydrochloride

To a solution of 1-phenyl-2-(phenylthio)-1H-imidazole-4-carbaldehyde(400 mg) in methanol (10 mL) was added 40% methylamine methanol solution(554 mg) at room temperature, and the mixture was stirred for 30 min.Sodium borohydride (108 mg) was added, and the mixture was stirred for15 min. Water was added, and the mixture was further stirred for 10 min.The reaction mixture was alkalified with saturated aqueous sodiumhydrogen carbonate solution, and extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent:ethylacetate), and dissolved in methanol (5 mL). 4 mol/L Hydrogenchloride-ethyl acetate solution (1 mL) was added, and the mixture wasconcentrated under reduced pressure. The residue was crystallized fromtetrahydrofuran to give the title compound as colorless crystals (yield347 mg, 66%).

¹H-NMR (DMSO-d₆) δ: 2.58 (3H, t, J=5.5 Hz), 4.11 (2H, t, J=5.5 Hz),7.07-7.10 (2H, m), 7.19-7.39 (5H, m), 7.47-7.54 (3H, m) 7.87 (1H, s),8.75 (1H, br), 9.40 (2H, br).

Reference Example 22 Ethyl 2,4-dioxo-4-phenylbutanoate

Sodium hydride (60% in oil, 4.0 g) was washed with hexane, suspended inN,N-dimethylformamide (30 mL), and a solution of acetophenone (10 g) anddiethyl oxalate (115 g) in N,N-dimethylformamide (50 mL) was added. Thereaction solution was stirred at room temperature, at 50° C. for 30 min,and concentrated under reduced pressure. 6 mol/L Hydrochloric acid wasadded to the residue, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to give the titlecompound as a colorless oil (yield 16 g, about 100%).

¹H-NMR (CDCl₃) δ: 1.42 (3H, t, J=8.8 Hz), 4.40 (2H, q, J=8.8 Hz), 7.09(1H, s), 7.40-7.70 (3H, m), 7.95-8.10 (2H, m), 1H not detected.

Reference Example 23 Ethyl 5-phenyl-1H-pyrazole-3-carboxylate

To a solution of ethyl 2,4-dioxo-4-phenylbutanoate (16.0 g) in ethanol(150 mL) was added hydrazine monohydrate (4.0 mL), and the mixture washeated under reflux for 3 hr. The reaction mixture was concentratedunder reduced pressure, and the residue was crystallized fromdiisopropyl ether to give the title compound as a pale-brown solid(yield 12.0 g, 67%).

¹H-NMR (CDCl₃) δ: 1.41 (3H, t, J=7.4 Hz), 4.41 (2H, q, J=7.4 Hz),4.80-6.50 (1H, brs), 7.12 (1H, s), 7.30-7.50 (3H, m), 7.79 (2H, d, J=7.9Hz).

Reference Example 24 Ethyl1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrazole-3-carboxylate

Sodium hydride (60% in oil, 612 mg) was washed with hexane, suspended inN,N-dimethylformamide solution (5 mL), and a solution of ethyl5-phenyl-1H-pyrazole-3-carboxylate (3.0 g) in N,N-dimethylformamide (10mL) was added dropwise. After the completion of the dropwise addition,the reaction mixture was stirred at room temperature for 30 min, andadded dropwise to an ice-cooled solution of p-toluenesulfonyl chloride(3.16 g) in N,N-dimethylformamide (10 mL). After the completion of thedropwise addition, the reaction mixture was stirred at room temperaturefor 1 hr, and concentrated under reduced pressure. Water was added tothe residue, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent:hexane-ethylacetate=9:1-1:1) to give the title compound as a colorless solid (yield1.037 g, 20%).

¹H-NMR (CDCl₃) δ: 1.42 (3H, t, J=7.4 Hz), 2.43 (3H, s), 4.43 (2H, q,J=7.4 Hz), 7.03 (1H, s), 7.30-7.50 (5H, m), 7.75-7.85% (2H, m), 8.07(2H, d, J=8.4 Hz).

Reference Example 251-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrazole-3-carbaldehyde

A solution of ethyl1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrazole-3-carboxylate (700 mg)in tetrahydrofuran (10 mL) was cooled to −78° C., and a 1.5 mol/Lsolution (3.8 mL) of diisobutylaluminum hydride in toluene was addeddropwise. After the completion of the dropwise addition, the mixture wasstirred at −78° C. for 30 min. 1 mol/L Hydrochloric acid was added, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. To a solution of the residue inacetonitrile (15 mL) were added tetra-n-propylammonium perruthenate (66mg), N-methylmorpholine N-oxide (442 mg) and molecular sieves 4A powder(1.0 g), and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was suspended in ethyl acetate and filtered through celite. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent:hexane-ethylacetate=9:1→2:1) to give the title compound as a pale-yellow solid(yield 224 mg, 36%).

¹H-NMR (CDCl₃) δ: 2.42 (3H, s), 6.72 (1H, s), 7.20-7.55 (7H, m), 7.59(2H, d, J=8.4 Hz), 10.02 (1H, s).

Reference Example 26 1-phenyl-2-(phenylthio)ethanone

To a suspension of 2-bromoacetophenone (10 g) and potassium carbonate(7.1 g) in ethanol (150 mL) was added thiophenol (5.2 mL) underice-cooling, and the mixture was stirred at room temperature for 12 hr.The insoluble material was filtered off, and the filtrate wasconcentrated under reduced pressure. Water was added to the residue, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated aqueous sodium hydrogen carbonate solution, water andsaturated brine in this order, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent:hexane-ethyl acetate=15:1) togive the title compound as yellow crystals (yield 11 g, 98%).

¹H-NMR (CDCl₃) δ: 4.28 (2H, s), 7.20-7.32 (3H, m), 7.37-7.41 (1H, m),7.44-7.50 (4H, m), 7.56-7.62 (1H, m), 7.93-7.97 (1H, m).

Reference Example 27 2-bromo-1-phenyl-2-(phenylthio)ethanone

To a solution of 1-phenyl-2-(phenylthio)ethanone (2.1 g) in acetic acid(20 mL) was added bromine (0.5 mL), and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was concentrated underreduced pressure, water was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogen carbonate solution, water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure to give the title compound as a yellow oil (yield 2.9 g, about100%).

¹H-NMR (CDCl₃) δ: 6.48 (1H, s), 7.40-7.44 (5H, m), 7.48-7.53 (3H, m),8.04-8.07 (2H, m).

Reference Example 28(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetonitrile

To a solution of bromoacetonitrile (22 g) in N,N-dimethylformamide (200mL) was added potassium phthalimide (34 g) under ice-cooling, and themixture was stirred at room temperature for 3 hr. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated aqueous sodium hydrogen carbonatesolution, water and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wasrecrystallized from ethanol to give the title compound as white crystals(yield 27 g, 80%).

¹H-NMR (CDCl₃) δ: 4.59 (2H, s), 7.79-7.85 (2H, m), 7.90-7.97 (2H, m).

Reference Example 292-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanethioamide

To a mixture of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetonitrile (15g), 4 mol/L hydrogen chloride-ethyl acetate solution (40 mL) andtetrahydrofuran (50 mL) was added O,O-diethyl dithiophosphate (15 mL),and the mixture was stirred at room temperature for 5 hr. Water wasadded to the reaction mixture, and the mixture was extracted with ethylacetate and tetrahydrofuran. The extract was washed twice with water,and then washed with saturated brine and saturated aqueous sodiumhydrogen carbonate solution, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was recrystallized fromethanol to give the title compound as white crystals (yield 9.0 g, 51%).

¹H-NMR (CDCl₃) δ: 4.69 (2H, s), 7.25 (1H, brs), 7.47 (1H, brs),7.75-7.79 (2H, m), 7.88-7.92 (2H, s).

Reference Example 302-{[4-phenyl-5-(phenylthio)-1,3-thiazol-2-yl]methyl}-1H-isoindole-1,3(2H)-dione

To a solution of 2-bromo-1-phenyl-2-(phenylthio)ethanone (3.2 g) inN,N-dimethylformamide (25 mL) was added2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanethioamide (2.3 g), andthe mixture was stirred at room temperature for 3 hr. Saturated aqueoussodium hydrogen carbonate solution was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated aqueous sodium hydrogen carbonate solution, water andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound as white crystals (yield3.0 g, 71%).

¹H-NMR (CDCl₃) δ: 5.19 (2H, s), 7.15-7.28 (5H, m), 7.33-7.40 (3H, m),7.75-7.79 (2H, m), 7.88-7.93 (4H, m).

Reference Example 311-[4-phenyl-5-(phenylthio)-1,3-thiazol-2-yl]methanamine

To a suspension of2-{[4-phenyl-5-(phenylthio)-1,3-thiazol-2-yl]methyl}-1H-isoindole-1,3(2H)-dione(0.53 g) in ethanol (5 mL) was added hydrazine monohydrate (0.1 mL), andthe mixture was stirred at 70° C. for 1 hr. The reaction mixture wascooled to room temperature, water was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogen carbonate solution, water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure to give the title compound as a yellow oil (yield 0.36 g, 97%).

¹H-NMR (CDCl₃) δ: 1.72 (2H, brs), 4.21 (2H, s), 7.16-7.30 (5H, m),7.35-7.43 (3H, m), 7.88-7.92 (2H, m).

Reference Example 32 tert-butyl{[4-phenyl-5-(phenylthio)-1,3-thiazol-2-yl]methyl}carbamate

To a solution of 1-[4-phenyl-5-(phenylthio)-1,3-thiazol-2-yl]methanamine(0.36 g) in ethyl acetate (5 mL) was added di-tert-butyl bicarbonate(0.3 mL), and the mixture was stirred at room temperature for 3 hr.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated aqueous sodiumhydrogen carbonate solution, water and saturated brine in this order,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent:hexane-ethyl acetate=5:1) to give the title compound as apale-yellow oil (yield 0.40 g, 84%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 4.63 (2H, brd, J=6.3 Hz), 5.27 (1H,brs), 7.16-7.30 (5H, m), 7.32-7.43 (3H, m), 7.87-7.91 (2H, m).

Reference Example 33 tert-butylmethyl{[4-phenyl-5-(phenylthio)-1,3-thiazol-2-yl]methyl}carbamate

Sodium hydride (60% in oil, 62 mg) was washed twice with hexane, andsuspended in N,N-dimethylformamide (10 mL). To the suspension was addeda solution of tert-butyl{[4-phenyl-5-(phenylthio)-1,3-thiazol-2-yl]methyl}carbamate (0.40 g) inN,N-dimethylformamide (2 mL) under ice-cooling, and the mixture wasstirred at the same temperature for 10 min. To the obtained mixture wasadded methyl iodide (0.1 mL) under ice-cooling, and the reaction mixturewas stirred at room temperature for 10 min. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated aqueous sodium hydrogen carbonatesolution, water and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent:hexane-ethylacetate=5:1) to give the title compound as a pale-yellow oil (yield 0.28g, 68%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, brs), 3.01 (3H, brs), 4.64-4.73 (2H, m),7.19-7.30 (5H, m), 7.36-7.40 (3H, m), 7.89-7.92 (2H, m).

Reference Example 34 tert-butylmethyl{[4-phenyl-5-(phenylsulfonyl)-1,3-thiazol-2-yl]methyl}carbamate

To a solution of tert-butylmethyl{[4-phenyl-5-(phenylthio)-1,3-thiazol-2-yl]methyl}carbamate (0.27g) in N,N-dimethylformamide (3 mL) was added 3-chloroperbenzoic acid(0.57 g) under ice-cooling, and the mixture was stirred at roomtemperature for 30 min. Aqueous sodium thiosulfate solution was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The extract was washed with saturated aqueous sodium hydrogen carbonatesolution, water and saturated brine in this order, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas dissolved in acetic acid (2 mL), 3-chloroperbenzoic acid (0.96 g)was added thereto, and the mixture was stirred at room temperature for30 min. Aqueous sodium thiosulfate solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated aqueous sodium hydrogen carbonate solution,water and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent:hexane-ethyl acetate=2:1) to give thetitle compound as a pale-yellow oil (yield 0.18 g, 63%).

¹H-NMR (CDCl₃) δ: 1.49-1.52 (9H, m), 3.01 (3H, s), 4.64-4.70 (2H, m),7.29-7.57 (10H, m).

Reference Example 352-phenyl-1-(2-thienylsulfonyl)-1H-imidazole-4-carbaldehyde

To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) intetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 603 mg)at room temperature, and the mixture was stirred for 15 min.Thiophene-2-sulfonyl chloride (2.39 g) was added to the reactionmixture, and the mixture was stirred for 1 hr. Saturated aqueous sodiumhydrogen carbonate solution was added, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent:hexane-ethyl acetate=3:2-2:3) to give the title compound as acolorless oil (yield 750 mg, 23%).

¹H-NMR (CDCl₃) δ: 6.94 (1H, dd, J=5.0, 4.0 Hz), 7.18 (1H, dd, J=4.0, 1.5Hz), 7.39-7.56 (5H, m), 7.69 (1H, dd, J=5.0, 1.5 Hz), 8.28 (1H, s), 9.94(1H, s).

Example 1N-methyl-1-[4-methyl-1-phenyl-5-(phenylsulfonyl)-1H-pyrrol-3-yl]methanaminehydrochloride

To a solution of4-methyl-1-phenyl-5-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (165 mg)in methanol (5 mL) was added 40% methylamine methanol solution (0.196mL), and the mixture was stirred at room temperature for 30 min. Sodiumborohydride (58 mg) was added to the reaction mixture, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasconcentrated under reduced pressure, water was added to the residue, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent:hexane-ethyl acetate=9:1→0:1).The obtained colorless oil was dissolved in ethyl acetate (5 mL), and 4mol/L hydrogen chloride-ethyl acetate solution (0.5 mL) was added. Theprecipitated crystals were collected by filtration, and dried underreduced pressure to give the title compound as a colorless solid (yield108 mg, 56%).

¹H-NMR (DMSO-d₆) δ: 2.47 (3H, s), 2.54 (3H, s), 3.98 (2H, s), 7.00-7.10(2H, m), 7.30-7.70 (9H, m), 8.92 (2H, br).

Example 2N-methyl-1-{3-methyl-5-[(4-methylphenyl)sulfonyl]-4-phenyl-1H-pyrrol-2-yl}methanaminehydrochloride

To a solution of3-methyl-5-[(4-methylphenyl)sulfonyl]-4-phenyl-1H-pyrrole-2-carbaldehyde(134 mg) in tetrahydrofuran (2 mL) were added 40% methylamine methanolsolution (0.4 mL) and methanol (2 mL) at room temperature, and themixture was stirred for 30 min. Sodium borohydride (23.6 mg) was addedto the reaction mixture, and the mixture was further stirred at roomtemperature for 30 min and concentrated under reduced pressure.Saturated aqueous sodium hydrogen carbonate solution was added to theresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated aqueous sodium hydrogen carbonate solution,water and saturated brine in this order, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent:ethylacetate:methanol=20:1) to give a free salt of the title compound (yield113 mg). To a solution of the obtained free salt in ethyl acetate (2 mL)was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), andthe mixture was stirred at room temperature for 15 min. The reactionmixture was concentrated under reduced pressure, and the residue wasrecrystallized from ethanol to give the title compound as white crystals(yield 32 mg, 21%).

¹H-NMR (DMSO-d₆) δ: 2.33 (3H, s), 2.57 (3H, s), 3.33 (3H, s), 4.14 (2H,s), 7.07-7.10 (2H, m), 7.25-7.28 (2H, m), 7.34-7.39 (5H, m), 8.87 (2H,brs), 12.20 (1H, brs).

Example 3N-methyl-1-{1-[(4-methylphenyl)sulfonyl]-2-phenyl-1H-imidazol-4-yl}methanamine0.5 oxalate

1-[(4-Methylphenyl)sulfonyl]-2-phenyl-1H-imidazole-4-carbaldehyde (1.00g) was dissolved in methanol (30 mL), 40% methylamine methanol solution(700 mg) was added at room temperature, and the mixture was stirred for30 min. Sodium borohydride (171 mg) was added at 5-10° C., and themixture was stirred for 30 min. 1 mol/L Hydrochloric acid was added atthe same temperature, and the mixture was further stirred for 30 min.The reaction mixture was alkalified with saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by basic silica gel column chromatography(eluent:hexane-ethyl acetate=1:1→0:1), dissolved in ethyl acetate (10mL), and crystallized by adding a solution (5 mL) of anhydrous oxalicacid (53 mg) in ethyl acetate to give the title compound as colorlesscrystals (yield 197 mg, 17%).

¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 2.57 (3H, s), 4.07 (2H, s), 7.32-7.47(8H, m), 7.53-7.57 (1H, m), 8.00 (1H, s), 2H not detected.

Example 41-[1-(mesitylsulfonyl)-2-phenyl-1H-imidazol-4-yl]-N-methylmethanamine0.5 oxalate

1-(Mesitylsulfonyl)-2-phenyl-1H-imidazole-4-carbaldehyde (2.20 g) wasdissolved in methanol (30 mL), 40% methylamine methanol solution (1.45g) was added at room temperature, and the mixture was stirred for 30min. Sodium borohydride (353 mg) was added at 5-10° C., and the mixturewas stirred for 30 min. 1 mol/L Hydrochloric acid (15 mL) was added atthe same temperature, and the mixture was further stirred for 30 min.The reaction mixture was alkalified with saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by basic silica gel column chromatography(eluent:hexane-ethyl acetate=1:1→0:1) to give a free salt of the titlecompound as a colorless oil (yield 1.47 g). The obtained free salt (0.85g) was dissolved in ethyl acetate (30 mL), and crystallized by adding asolution of anhydrous oxalic acid (208 mg) in ethyl acetate (30 mL) togive the title compound as colorless crystals (yield 932 mg, 62%).

¹H-NMR (DMSO-d₆) δ: 2.13 (6H, s), 2.24 (3H, s), 2.59 (3H, s), 4.12 (2H,s), 6.97 (2H, s), 7.07-7.10 (2H, m), 7.25-7.50 (3H, m), 7.99 (1H, s), 2Hnot detected.

Example 5N,N-dimethyl-1-{1-[(4-methylphenyl)sulfonyl]-2-phenyl-1H-imidazol-4-yl}methanamine0.5 oxalate

A mixture of1-[(4-methylphenyl)sulfonyl]-2-phenyl-1H-imidazole-4-carbaldehyde (300mg), methylammonium chloride (225 mg), molecular sieves 3A (2.0 g) andethanol (10 mL) was stirred at 60° C. for 1 hr. The reaction mixture wascooled, sodium borohydride (105 mg) was added at 5-10° C., and themixture was stirred for 30 min. Saturated aqueous sodium hydrogencarbonate was added at the same temperature, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent:hexane-ethyl acetate=2:3→0:1), and crystallizedby adding a solution (10 mL) of anhydrous oxalic acid in ethyl acetateto give the title compound as colorless crystals (yield 106 mg, 29%).

¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 2.74 (6H, s), 4.19 (2H, s), 7.32-7.57(9H, m), 8.06 (1H, s), 2H not detected.

Example 6N-methyl-1-[2-phenyl-1-(pyridin-3-ylsulfonyl)-1H-imidazol-4-yl]methanaminefumarate

2-Phenyl-1-(pyridin-3-ylsulfonyl)-1H-imidazole-4-carbaldehyde (200 mg)was dissolved in a solution of methylammonium chloride (216 mg) inmethanol (10 mL), and the mixture was stirred for 30 min. Sodiumtriacetoxyborohydride (203 mg) was added, and the mixture was stirredfor 5 hr. The reaction mixture was concentrated under reduced pressureat 30° C., saturated aqueous sodium hydrogen carbonate solution wasadded to the residue, and the mixture was extracted with ethyl acetate(60 mL). The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(eluent:ethyl acetate-methanol=1:0→7:3), dissolved in ethyl acetate (20mL), and crystallized by adding a solution of anhydrous fumaric acid (75mg) in methanol (2 mL) to give the title compound as colorless crystals(yield 74 mg, 26%).

¹H-NMR (DMSO-d₆) δ: 2.47 (3H, s), 3.91 (2H, s), 6.51 (2H, s), 7.31-7.47(4H, m), 7.52-7.58 (1H, m), 7.59-7.63 (1H, m), 7.93-7.97 (2H, m), 8.61(1H, d, J=2.2 Hz), 8.89 (1H, dd, J=4.9, 1.5 Hz), 3H not detected.

Example 71-{1-[(3-methoxyphenyl)sulfonyl]-2-phenyl-1H-imidazol-4-yl}-N-methylmethanaminefumarate

1-[(3-Methoxyphenyl)sulfonyl]-2-phenyl-1H-imidazole-4-carbaldehyde (620mg) was dissolved in a solution of methylammonium chloride (612 mg) inmethanol (40 mL), and the mixture was stirred for 30 min. Sodiumtriacetoxyborohydride (1.15 g) was added, and the mixture was stirredfor 1 hr. The reaction mixture was concentrated under reduced pressureat 30° C., saturated aqueous sodium hydrogen carbonate solution wasadded to the residue, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas dissolved in ethyl acetate (20 mL), and crystallized by adding asolution of anhydrous fumaric acid (216 mg) in methanol (4 mL) to givethe title compound as colorless crystals (yield 317 mg, 37%).

¹H-NMR (DMSO-d₆) δ: 2.45-2.48 (3H, m), 3.70 (3H, s), 3.88-3.95 (2H, m),6.50 (2H, s), 6.89-6.90 (1H, m), 7.12-7.15 (1H, m), 7.29-7.56 (7H, m)7.92-7.97 (1H, m), 3H not detected.

Example 81-{1-[(2,6-difluorophenyl)sulfonyl]-2-phenyl-1H-imidazol-4-yl}-N-methylmethanaminefumarate

A mixture of1-[(2,6-difluorophenyl)sulfonyl]-2-phenyl-1H-imidazole-4-carbaldehyde(1.23 g), methylammonium chloride (1.19 g) and methanol (40 mL) wasstirred at room temperature for 30 min, sodium triacetoxyborohydride(2.25 g) was added, and the mixture was further stirred for 1 hr. Thereaction mixture was concentrated under reduced pressure at 30° C.,saturated aqueous sodium hydrogen carbonate solution was added to theresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was dissolved inethyl acetate (40 mL), and crystallized by adding a solution ofanhydrous fumaric acid (410 mg) in methanol (4 mL) to give the titlecompound as colorless crystals (yield 750 mg, 44%).

¹H-NMR (DMSO-d₆) δ: 2.47 (3H, s), 3.94 (2H, s), 6.50 (2H, s), 7.21-7.38(6H, m), 7.44-7.50 (1H, m), 7.78-7.88 (1H, m), 7.93 (1H, s), 3H notdetected.

Example 91-{1-[1-benzothien-2-ylsulfonyl]-2-phenyl-1H-imidazol-4-yl}-N-methylmethanaminefumarate

A mixture of1-(1-benzothien-2-ylsulfonyl)-2-phenyl-1H-imidazole-4-carbaldehyde (1.25g), methylammonium chloride (1.15 g) and methanol (40 mL) was stirred atroom temperature for 30 min, sodium triacetoxyborohydride (2.16 g) wasadded, and the mixture was further stirred for 1 hr. The reactionmixture was concentrated under reduced pressure at 30° C., saturatedaqueous sodium hydrogen carbonate solution was added to the residue, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent:ethyl acetate), dissolved inethyl acetate (40 mL), and crystallized by adding a solution ofanhydrous fumaric acid (394 mg) in methanol (4 mL) to give the titlecompound as colorless crystals (yield 1.17 g, 69%).

¹H-NMR (DMSO-d₆) δ: 2.49-2.50 (3H, m), 3.97-3.98 (2H, m), 6.53 (2H, s),7.44 (4H, d, J=4.3 Hz), 7.52-7.65 (3H, m), 7.97-8.01 (3H, m), 8.11-8.13(1H, m), 3H not detected.

Example 10N-methyl-1-[1-phenyl-2-(phenylsulfonyl)-1H-imidazol-4-yl]methanaminedihydrochloride

To a solution ofN-methyl-1-[1-phenyl-2-(phenylthio)-1H-imidazol-4-yl]methanamine (170mg) in acetone (40 mL) and water (20 mL) was added an aqueous solution(40 mL) of oxone (2.13 g), and the mixture was stirred at 55° C. for 2hr. Sodium thiosulfate pentahydrate (1.15 g) was added to the reactionmixture, and the mixture was stirred for 1 hr. Saturated aqueous sodiumhydrogen carbonate solution was added, and the mixture was extractedwith ethyl acetate. The extract was further extracted twice with a mixedsolution of ethyl acetate-tetrahydrofuran (1:1). The combined extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent:ethylacetate-methanol=7:3→1:0) and dissolved in methanol (5 mL). 4 mol/LHydrogen chloride-ethyl acetate solution (1 mL) was added and themixture was concentrated under reduced pressure. The residue wascrystallized from tetrahydrofuran to give the title compound ascolorless crystals (yield 14 mg, 8%).

¹H-NMR (DMSO-d₆) δ: 2.58 (3H, s), 4.11 (2H, s), 7.27-7.29 (2H, m),7.50-7.62 (7H, m), 7.73-7.81 (2H, m), 3H not detected.

Example 11N-methyl-1-{1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrazol-3-yl}methanaminehydrochloride

To a solution of1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrazole-3-carbaldehyde (220mg) and methylammonium chloride (455 mg) in methanol (5 mL) was addedsodium borohydride (127 mg), and the mixture was stirred at roomtemperature for 18 hr. The reaction mixture was concentrated underreduced pressure, saturated aqueous sodium hydrogen carbonate solutionwas added to the residue, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography(eluent:hexane-ethyl acetate=9:1→0:1). The obtained colorless oil wasdissolved in ethyl acetate (5 mL), 4 mol/L hydrogen chloride-ethylacetate solution (0.5 mL) was added, and the mixture was concentratedunder reduced pressure. The residue was recrystallized from ethanol togive the title compound as a colorless solid (yield 70 mg, 27%).

¹H-NMR (DMSO-d₆) δ: 2.39 (3H, s), 2.55 (3H, s), 4.18 (2H, s), 6.76 (1H,s), 7.30-7.60 (9H, s), 9.35 (2H, br).

Example 12N-methyl-1-[4-phenyl-5-(phenylsulfonyl)-1,3-thiazol-2-yl]methanaminehydrochloride

To a solution of tert-butylmethyl{[4-phenyl-5-(phenylsulfonyl)-1,3-thiazol-2-yl]methyl}carbamate(0.18 g) in ethanol (2 mL) was added 4 mol/L hydrogen chloride-ethylacetate solution (2 mL) at room temperature, and the mixture was stirredfor 14 hr. The reaction mixture was concentrated under reduced pressure,and the residue was recrystallized from ethanol to give the titlecompound as white crystals (yield 80 mg, 53%).

¹H-NMR (CDCl₃) δ: 2.76 (3H, s), 4.46 (2H, s), 7.26-7.62 (10H, m), 10.31(2H, brs).

Example 13N-methyl-1-(2-phenyl-1-(2-thienylsulfonyl)-1H-imidazol-4-yl)methanaminefumarate

2-Phenyl-1-(2-thienylsulfonyl)-1H-imidazole-4-carbaldehyde (730 mg) wasdissolved in a solution of methylammonium chloride (775 mg) in methanol(20 mL), and the mixture was stirred for 30 min. Sodiumtriacetoxyborohydride (1.46 g) was added, and the mixture was stirredfor 1 hr. The reaction mixture was concentrated under reduced pressureat 30° C., saturated aqueous sodium hydrogen carbonate solution wasadded to the residue, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by basic silica gel column chromatography (eluent:ethylacetate-ethyl acetate-methanol (97:3)), dissolved in ethyl acetate (10mL), and crystallized by adding a solution of anhydrous fumaric acid(267 mg) in methanol (2 mL) to give the title compound as colorlesscrystals (yield 627 mg, 61%).

¹H-NMR (DMSO-d₆) δ: 2.46 (3H, s), 3.90 (2H, s), 6.50 (2H, s), 7.17 (1H,dd, J=5.0, 4.0 Hz), 7.40-7.58 (6H, m), 7.86 (1H, s), 8.16 (1H, dd,J=5.0, 1.4 Hz), 3H not detected.

Experimental Example 1

Proton potassium—adenosine triphosphatase (H⁺,K⁺-ATPase) inhibitoryactivity test

According to the method [Biochim. Biophys. Acta, 728, 31 (1983)] ofWallmark et al., a gastric mucous membrane microsomal fraction wasprepared from the stomach of swine. First, the stomach was removed,washed with tap water, immersed in 3 mol/L brine, and the surface of themucous membrane was wiped with a paper towel. The gastric mucousmembrane was detached, chopped, and homogenized in a 0.25 mol/Lsaccharose solution (pH 6.8) containing 1 mmol/L EDTA and 10 mmol/Ltris-hydrochloric acid using polytron (Kinematica). The obtainedhomogenate was centrifuged at 20,000×g for 30 min and the supernatantwas centrifuged at 100,000×g for 90 min. The precipitate was suspendedin 0.25 mol/L saccharose solution, superimposed on a 0.25 mol/Lsaccharose solution containing 7.5% Ficoll, and centrifuged at 100,000×gfor 5 hr. The fraction containing the interface between the both layerswas recovered, and centrifugally washed with 0.25 mol/L saccharosesolution.

The obtained microsomal fraction was used as a proton,potassium—adenosine triphosphatase standard product.

To 40 μL of a 50 mmol/L HEPES-tris buffer (5 mmol/L magnesium chloride,10 mmol/L potassium chloride, 10 μmol/L valinomycin, pH=6.5) containing2.5 μg/mL (based on the protein concentration) of the enzyme standardproduct was added a test compound (5 μL) dissolved in a 10% aqueousdimethyl sulfoxide solution, and the mixture was incubated at 37° C. for30 min. The enzyme reaction was started by adding 5 μL of a 2 mmol/Ladenosine triphosphate tris salt solution (50 mmol/L HEPES-tris buffer(5 mmol/L magnesium chloride, pH 6.5)). The enzyme reaction wasperformed at 37° C. for 20 min, and 15 μL of a malachite green solution(0.12% malachite green solution in sulfuric acid (2.5 mol/L), 7.5%ammonium molybdate and 11% Tween 20 were mixed at a ratio of 100:25:2)was added to quench the reaction. After allowing to stand at roomtemperature for 15 min, the resulting reaction product of inorganicphosphorus with malachite green was colorimetrically determined at awavelength of 610 nm. In addition, the amount of the inorganicphosphoric acid in the reaction solution free of potassium chloride wasmeasured in the same manner, which was subtracted from the inorganicphosphoric acid amount in the presence of potassium chloride todetermine the proton, potassium—adenosine triphosphatase activity. Theinhibitory rate (%) was determined from the activity value of thecontrol activity value and the activity values of various concentrationsof the test compound, and the 50% inhibitory concentration (IC₅₀) of theproton, potassium-adenosine triphosphatase was determined. The resultsare shown in Table 1.

TABLE 1 Example compound IC₅₀ (μM) 1 0.18 5 0.16 7 0.03 12 0.17

INDUSTRIAL APPLICABILITY

Compound (I) of the present invention shows a superior proton pumpinhibitory action. Conventional proton pump inhibitors such asomeprazole, lansoprazole and the like form a covalent bond with acysteine residue of H⁺/K⁺-ATPase, and irreversibly inhibit the enzymeactivity. In contrast, compound (I) inhibits proton pump (H⁺/K⁺-ATPase)activity in a reversible and K⁺ antagonist-like inhibitory manner, andconsequently suppresses acid secretion. Therefore, it is sometimescalled a potassium-competitive acid blocker (P-CAB), or an acid pumpantagonist (APA). Compound (I) rapidly expresses the action and showsthe maximum efficacy from the initial administration. Furthermore, itcharacteristically shows less influence of metabolic polymorphism(variation between patients) and long duration of action. Accordingly,the present invention can provide a clinically useful agent for theprophylaxis or treatment of peptic ulcer (e.g., gastric ulcer, duodenalulcer, anastomotic ulcer, ulcer caused by non-steroidalanti-inflammatory agent, ulcer due to postoperative stress etc.),Zollinger-Ellison syndrome, gastritis, erosive esophagitis, refluxesophagitis, symptomatic gastroesophageal reflux disease (SymptomaticGERD), Barrett's esophagus, functional dyspepsia including NUD (NonUlcer Dyspepsia), gastric cancer, stomach MALT lymphoma or hyperacidity;or a suppressant of upper gastrointestinal hemorrhage due to pepticulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress; andthe like. Since compound (I) shows low toxicity and is superior inwater-solubility, in vivo kinetics and efficacy expression, it is usefulas a pharmaceutical composition. Moreover, since compound (I) is stableeven under acidic conditions, it can be administered orally as aconventional tablet and the like without formulating into anenteric-coated preparation. This has an advantageous consequence thatthe preparation (tablet and the like) can be made smaller, and can beeasily swallowed by patients having difficulty in swallowing,particularly the elderly and children. In addition, since it is free ofa sustained release effect afforded by enteric-coated preparations, agastric acid secretion-suppressive action is expressed rapidly, andsymptoms such as pain and the like can be alleviated rapidly.

This application is based on a patent application No. 2006-100651 filedin Japan, the contents of which are incorporated in full herein by thisreference.

1.-12. (canceled)
 13. A method of preventing ulcer caused by anon-steroidal antiinflammatory agent; or a method of treating orpreventing Zollinger-Ellison syndrome, Barrett's esophagus, functionaldyspepsia, gastric cancer, stomach MALT lymphoma or gastrichyperacidity; or a method of inhibiting upper gastrointestinalhemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagicgastritis or invasive stress, the method comprising administering aneffective amount a compound represented by the formula

wherein ring C is a saturated or unsaturated 5-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, ring D is a saturated or unsaturated 6-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, R^(1a) and R^(1b) are each an optionally substituted arylgroup or an optionally substituted heteroaryl group, R^(2a) and R^(2b)are each an optionally substituted alkyl group, an optionallysubstituted aryl group or an optionally substituted heteroaryl group,R^(6a), R^(7a), R^(6b) and R^(7b) are each absent, or a hydrogen atom, alower alkyl group, a halogen atom or a cyano group, R^(3a) and R^(3b)are each an aminomethyl group optionally substituted by 1 or 2 loweralkyl groups, R^(8b) is absent, or a hydrogen atom, a lower alkyl group,a halogen atom, a cyano group or an oxo group, excluding a compoundrepresented by the formula

wherein each symbol is as defined above, or a salt thereof, to a mammal.14. (canceled)
 15. A method of eradicating Helicobacter pylori in amammal, the method comprising administering to the mammal an effectiveamount a compound represented by the formula

wherein ring C is a saturated or unsaturated 5-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, ring D is a saturated or unsaturated 6-membered ring groupoptionally having, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms selected from a nitrogen atom, an oxygen atom and asulfur atom, R^(1a) and R^(1b) are each an optionally substituted arylgroup or an optionally substituted heteroaryl group, R^(2a) and R^(2b)are each an optionally substituted alkyl group, an optionallysubstituted aryl group or an optionally substituted heteroaryl group,R^(6a), R^(7a), R^(6b) and R^(7b) are each absent, or a hydrogen atom, alower alkyl group, a halogen atom or a cyano group, R^(3a) and R^(3b)are each an aminomethyl group optionally substituted by 1 or 2 loweralkyl groups, R^(8b) is absent, or a hydrogen atom, a lower alkyl group,a halogen atom, a cyano group or an oxo group, excluding a compoundrepresented by the formula

wherein each symbol is as defined above, or a salt thereof, incombination with 1 to 3 other active ingredients.
 16. The method ofclaim 15, wherein the other active ingredients are selected from (i)penicillin antibiotics and/or (ii) macrolide antibiotics.
 17. The methodof claim 15, wherein the other active ingredients are selected fromimidazole compounds.